逼尿肌细胞、ICCs细胞自发性钙瞬变发生及调控机制的研究
|
摘要
背景及目的:
膀胱逼尿肌是一种特殊的平滑肌组织,逼尿肌组织在受到神经支配的同时,是否存在类似心脏和胃肠道平滑肌的自发性兴奋,曾经是个认识不清的问题。我科对之进行了较系统的研究后发现:①离体条件下膀胱逼尿肌肌条可出现自发的兴奋性收缩;②离体膀胱逼尿肌条在多种神经递质拮抗剂“鸡尾酒”式的混合阻断下,仍然能产生收缩。以上研究结果及国外相关研究让我们认识到:逼尿肌组织具有自主产生兴奋的能力,这种自发性肌源性兴奋并不依赖于神经因素的作用而存在。
我们的实验研究还发现,在膀胱流出道梗阻和神经源性异常引起的逼尿肌不稳定(Detrusor instability,DI)时,这种肌源性的自发兴奋和收缩明显增强,表现为:不稳定逼尿肌肌条与正常逼尿肌肌条相比,自发性收缩的幅度和频率明显增加;同等张力负荷下不稳定逼尿肌肌条的自发性收缩频率较正常逼尿肌肌条明显增加。膀胱逼尿肌兴奋性增高亦常见于临床,如继发于神经源性膀胱功能障碍及膀胱出口梗阻时。这一异常现象的发生目前被归咎为两个基本的机制:①神经源性学说。这一学说居主导地位,以de Groat为代表,强调所有兴奋性改变均源于神经因素,或为神经因素的延续效应,主要是表现在神经受体的数量和功能的上调。②肌源性学说。以Brading为代表,认为兴奋性改变除神经因素作用外,尚有肌源性异常因素参与,包括逼尿肌肌细胞的兴奋性增高、细胞间信号传导功能的加强、逼尿肌细胞与神经节细胞的联系增加,以及膀胱内可能存在的起搏细胞功能数量及功能的上调等。对膀胱肌源性兴奋的机制进行研究将有望为相关膀胱功能障碍性疾病开创新的治疗策略提供理论基础。
在膀胱兴奋的肌源性学说这一理论中,膀胱内是否存在具有起搏功能的细胞至关重要,也一直为人们所重视。Cajal间质细胞(Interstitial cells of cajal,ICC)是一类与平滑肌细胞在形态及功能上均不相同细胞,业已证明这些细胞是胃肠道、输尿管等器官的起搏细胞,这些器官的平滑肌自发性兴奋均起源于其中ICCs细胞。McCloskey等及Shafik等采用c-kit特异性标记的方法,先后证实了在豚鼠和人的膀胱中存在ICCs细胞,这种细胞呈长梭形,在去极化时不能产生自发收缩,有别于正常的逼尿肌肌细胞,更为特异的是这种细胞c-kit表达呈阳性,它们主要沿肌束分布,并可产生钙活动,与神经和平滑肌细胞也有广泛的联系,极可能是起搏细胞或是兴奋调节细胞。后续ICCs细胞功能方面的研究发现,ICCs细胞具有自动除极的外向电流,c-kit的特异性阻断剂Glivec可显著抑制逼尿平滑肌束的自发性动作电位和兴奋收缩能力;提示ICCs细胞可能具备自动除极化,完成自动起搏的能力,这从功能学上肯定了ICCs细胞的存在以及其作为起搏细胞的可能性。但ICCs细胞是否是膀胱逼尿肌自发性兴奋的起搏细胞,目前尚无明确结论;开展膀胱逼尿肌组织中相关研究,特别对ICCs细胞和平滑肌细胞的自发性兴奋特征进行对比,将为阐明膀胱ICCs细胞是否是膀胱起搏细胞及其可能具有的功能提供重要的研究证据。
钙离子是细胞内信号转导重要的第二信使,在平滑肌细胞中,钙自发性释放入胞浆导致的钙火花(Ca~(2+) spark)及细胞外钙内流诱导内质网中钙释放(Ca~(2+) induced Ca~(2+) release, CICR)均是通过Ⅱ型Ryanodine受体(RyR2)完成的。细胞钙瞬变(Ca~(2+) transients)与动作电位的发生关系密切,是动作电位发生的重要信号。动作电位相关的平滑肌细胞膜去极化可致细胞膜上电压门控的钙离子通道开放,细胞外钙内流随后通过CICR作用诱导细胞内质网(sarcoplasmic reticulum,SR)中的钙释放入胞浆,导致细胞浆内钙离子浓度瞬间升高,引起细胞发生钙瞬变和平滑肌收缩。
环腺苷二磷酸核糖(Cyclic adenosine diphosphate ribose,cADPR)是细胞内烟酰胺腺嘌呤二核苷酸(NAD+)的代谢产物,是目前为止除钙离子外,平滑肌细胞内对细胞内质网上RyR2有调节作用的又一重要第二信使。以往的研究发现,cADPR可通过调控平滑肌细胞内质网RyR2开放对平滑肌细胞钙瞬变的发生及钙瞬变特征产生显著调节作用,其具体机制为:cADPR可通过影响细胞自发性瞬时外向电流(spontaneous transient outward currents,STOCs)、自发性瞬时内向电流(spontaneous transient outward currents,STICs)影响平滑肌细胞去极化,并可通过影响钙诱导的钙释放(CICR)影响平滑肌细胞细胞钙瞬变的幅度。但目前cADPR调节平滑肌细胞内质网钙释放的作用机制仍不清楚,研究结论还存在较大的矛盾。探讨cADPR调节平滑肌细胞内质网中钙释放这一cADPR调控细胞钙瞬变发生关键环节的机制,将为深入了解cADPR调控平滑肌细胞钙瞬变的过程提供实验依据。
考虑到细胞钙瞬变与细胞动作电位的发生密切相关,cADPR可通过影响细胞内质网中钙释放进而调控平滑肌钙瞬变的发生及其特征,本研究拟以细胞钙瞬变为观察指标,比较分析ICCs细胞和平滑肌细胞自发性钙瞬变的特征及发生机制;并以反映平滑肌细胞内钙释放的STOCs和钙火花(Ca~(2+) spark)为观察指标,通过利用FKBP12.6基因敲除小鼠,对cADPR调节平滑肌细胞内质网中钙释放的机制进行探讨。本研究将有助于我们深入对平滑肌细胞和ICCs细胞自发性钙瞬变特征、发生和调控的认识,并为阐明膀胱ICCs细胞的功能提供初步的研究证据。本研究拟从以下四个方面展开:
第一:利用免疫荧光单染及双染的方法,观察ICCs细胞在逼尿肌组织中的分布及与平滑肌细胞的关系,为后续平滑肌细胞和ICCs细胞自发性钙瞬变的检测提供参考;
第二:对膀胱逼尿肌组织铺片中的平滑肌细胞和相邻ICCs细胞自发性钙瞬变进行检测,比较分析两种细胞自发性钙瞬变的频率和幅度,初步探讨平滑肌相邻ICCs细胞可能的功能;
第三:检测细胞外钙内流及细胞钙库中钙释放干预因素对细胞自发性钙瞬变的影响,探讨细胞外钙内流及细胞内质网中钙释放入胞浆在两种细胞自发性钙瞬变发生的作用;
第四:对比野生型和FKBP12.6基因敲除小鼠中cADPR对膀胱平滑肌细胞STOCs、钙火花及细胞内质网总钙含量的影响,探讨cADPR调节平滑肌细胞内质网中钙释放这一cADPR调控细胞钙瞬变发生关键环节的机制,为深入了解cADPR调控平滑肌细胞钙瞬变的机制提供实验依据。
方法:本研究采用2-3月龄SD大鼠为研究对象。首先利用免疫荧光方法检测逼尿肌组织中ICCs细胞的分布及其与平滑肌细胞的关系。随后参照Hashitani等[18]的方法制作膀胱组织铺片,于记录Chamber底部Physiological saline生理液灌流保持肌条铺片活性。待肌条自发性收缩活动出现后,Fluo-4 AM负载肌条铺片,激光共聚焦显微镜观察铺片中平滑肌细胞和ICCs细胞自发性钙瞬变,随后分别观察L型、T型钙离子通道阻断剂Nimodipine、Nicl2,内质网IP3受体拮抗剂2-aminoethoxy diphenylborate (2-APB),内质网RyR受体拮抗剂Ryanodine,内质网RyR受体激动剂Caffeine,内质网钙泵抑制剂Thapsigargin及无钙、高钙生理液对平滑肌细胞和ICCs细胞自发性钙瞬变的影响,探讨平滑肌细胞和ICCs细胞自发性钙瞬变产生、调控的机制。
最后利用FKBP12.6基因敲除小鼠探讨cADPR调节膀胱平滑肌细胞内质网中钙释放的机制。通过PCR方法对敲除小鼠的基因表型进行鉴定。通过膜片钳记录cADPR对平滑肌细胞自发性瞬时外向电流(spontaneous transient out currents,STOCs)的影响,使用膜片钳和激光共聚焦显微镜共记录的方法,同步观察cADPR对平滑肌细胞STOCs和钙火花(Ca~(2+) spark)的影响。利用激光共聚焦显微镜观察cADPR对膀胱平滑肌细胞细胞钙火花特征的影响,并通过Thapsigargin预处理了解内质网钙泵是否参与cADPR调节平滑肌细胞中钙释放作用。利用Western blot实验,检测cADPR作用后,FKBP12.6从RyR2上释放入胞浆的情况。利用双Puff系统,通过瞬时使用10mM Caffeine,探讨cADPR对平滑肌细胞内质网中总钙含量的影响。
结果:
1. SD大鼠膀胱逼尿肌组织中存在ICCs细胞,ICCs细胞在逼尿肌肌束旁、肌束间和肌束内均有分布;ICCs细胞与平滑肌细胞、神经末梢在空间结构上紧密相邻;肌束旁和肌束间的ICCs细胞有时可连成一片,有可能成为相邻肌束之间联系的“桥梁”;
2.逼尿肌组织铺片中平滑肌细胞自发性钙瞬变的特征如下:
(1)逼尿肌组织铺片Fluo-4刚负载完成时,平滑肌束中平滑肌细胞自发性钙瞬变多不同步;热的生理液灌流20-30min后,平滑肌束中平滑肌细胞自发性钙瞬变趋于同步;
(2)平滑肌细胞钙瞬变多起源于肌束边缘,而后传递到肌束的另一侧;部分钙瞬变可起源于肌束中部,而后向肌束两侧传递;
(3)平滑肌细胞钙瞬变在肌束内纵向传递几乎无时间延迟,但其在肌束内横向传递有一定的时间延迟;
(4)观察到相邻的肌束间可通过肌束间细胞进行钙瞬变的传递。
3.成功同时记录到膀胱逼尿肌组织铺片中平滑肌细胞和肌束旁ICCs细胞的自发性钙瞬变,平滑肌细胞自发性钙瞬变频率相对较快,而肌束旁ICCs细胞的自发性钙瞬变频率相对较慢;
4.膀胱逼尿肌组织铺片中的药理实验研究发现:
(1) L型钙离子通道阻断剂Nimodipine能完全抑制平滑肌细胞的自发性钙瞬变,但对ICCs细胞的自发性钙瞬变无显著影响;T型钙离子通道阻断剂Nicl2可明显降低平滑肌细胞的自发性钙瞬变的频率,对平滑肌细胞钙瞬变的幅度及ICCs细胞的自发性钙瞬变无明显影响;
(2) Ryanodine,Caffeine,2-APB,和Thapsigargin均可对平滑肌细胞的自发性钙瞬变产生显著的抑制作用,但不能完全消除平滑肌细胞的自发性钙瞬变的发生;
(3) Ryanodine,Caffeine,2-APB,和Thapsigargin及无钙生理液均可完全抑制ICCs细胞的自发性钙瞬变,高钙生理液可显著增加ICCs细胞自发性钙瞬变的频率而降低其频率。
5.成功对FKBP12.6基因敲除小鼠进行了基因表型鉴定。经鉴定,基因敲除小鼠繁殖后,表现为三种基因表型:纯合子(FKBP12.6 -/-)、杂合子(FKBP12.6 +/-)和野生型(FKBP12.6 +/+);
6. cADPR可显著增大野生型小鼠膀胱平滑肌细胞的STOCs,对FKBP12.6基因敲除小鼠(纯和子)平滑肌细胞STOCs却无明显影响;
7.膜片钳和激光共聚焦显微镜共记录的研究结果发现,cADPR可显著增强野生型小鼠膀胱平滑肌细胞的STOCs及钙火花,但对FKBP12.6基因敲除小鼠平滑肌细胞STOCs及钙火花却无明显影响;
8. cADPR对野生型小鼠膀胱平滑肌细胞钙火花有显著影响,而对FKBP12.6基因敲除小鼠平滑肌细胞钙火花却无明显调节作用。具体表现为:cADPR可显著提高野生型小鼠膀胱平滑肌细胞钙火花的频率、幅度及FWHM距离,明显延长其上升时间和半数衰减时间;而cADPR对FKBP12.6基因敲除小鼠细胞钙火花的上述特征性指标无明显影响;
9.内质网钙泵抑制剂Thapsigargin对cADPR调节平滑肌细胞自发性钙释放的作用无明显影响;
10. Western blot实验证实,cADPR可使FKBP12.6从RyR2上脱落下来,释放入胞浆中;
11. cADPR可显著降低野生型小鼠膀胱平滑肌细胞内质网中的总钙含量,而对FKBP12.6基因敲除小鼠内质网中的总钙含量却无明显影响。
结论:
1.膀胱平滑肌自发性钙瞬变在肌束中纵向传递和横向传递的延迟不同可能来自传递机制的不同,而肌束间钙瞬变的传递增强可能参与DI的发生;
2.热生理液灌流使肌束中平滑肌细胞自发性钙瞬变趋于同步及钙瞬变多起源于肌束边缘提示:膀胱逼尿肌组织中存在起搏细胞的可能性很大,可能是膀胱起搏细胞的是:①肌束一侧的平滑肌细胞和②肌束旁或肌束内ICCs细胞;钙瞬变也可起源于肌束中部,提示不同部位的膀胱平滑肌组织起搏细胞的分布可能存在差异;
3.膀胱组织铺片中平滑肌细胞自发性钙瞬变频率明显快于肌束旁ICCs细胞,提示平滑肌细胞自发性钙瞬变起源于肌束旁ICCs细胞的可能性不大;考虑到目前肌束内ICCs细胞自发性钙瞬变尚不能进行检测,及目前技术手段对ICCs细胞自发性钙瞬变观察的限制,不排除肌束内和具有不同功能的肌束旁ICCs细胞是膀胱起搏细胞的可能性;
4.细胞外钙通过L型钙离子通道入胞在平滑肌细胞自发性钙瞬变发生中起主要作用,而细胞内钙库中的钙释放入胞浆可能起辅助作用;Ca~(2+)通过T型钙离子通道入胞则可影响细胞自发性钙瞬变的发生频率;
5.细胞外钙通过非L型钙离子通道入胞及胞内钙库中的钙释放均参与ICCs细胞自发性钙瞬变的发生;参与ICCs细胞自发性钙瞬变发生的细胞膜上的非L型钙离子通道可能是①钠钙交换体NCX、②T型钙离子通道和③TRP(瞬时受体势)离子通道中的多个通道;
6. cADPR调节平滑肌细胞内质网钙释放的机制是:使FKBP12.6从RyR2上脱落下来,导致RyR2通道开放明显增强,内质网中钙离子经RyR2通道释放入胞浆显著增加。
Bladder is a hollow muscular organ collects urine excreted by the kidneys prior to disposal by urination. The detrusor muscle is a layer of the urinary bladder wall made of smooth muscle fibers arranged in spiral, longitudinal, and circular bundles. As a speical smooth muscle tissue, the detrusor muscle is double controlled by splanchnic nerve and somatic nerves. Whether the detrusor muscle can generate spontaneous contraction like heart and gastrointestinal tract do was ever a mysterious question.Our previous research have demonstrated several interesting phenomenons:first, all the strips isolated from bladder exhibit spontaneous contraction activity under certain tension load, and the unstable strips will develop spontaneous contraction under little tension load; second, when under the same tension load, the frequency of unstable detrusor strips increases more significantly than that of normal detrusor; third, the spontaneous contraction is little affected by neural factors. These phenomenons indicated that the spontaneous contraction of detrusor strips may not be neurogenic, and the detrusor should have the ability of generating spontaneous excitability itself.
It is also notable that the detrusor muscle exhibited significant increased activity of spontaneous contraction in a urological condition termed as DI(Detrusor instability) induced by bladder outlet obstruction or abnormal nerve function. Compared with normal detrusor strips, Smaller tension load is sufficient to induced spontaneous contractions in unstable detrusor strips.When under the same tension load, the frequency of unstable detrusor strips increases more significantly than that of normal detrusor strips.The enhanced spontaneous contraction also were observed in patients with overactive bladder (OAB)who suffered nearogenic bladder dysfunction and partial bladder outlet obstruction.The etiology of OAB is unclear, and indeed there may be multiple possible causes.In present,two different mechanism were made to explanation cause and development of OAB.① neurogenic mechanism:de Groat is one of supporter of neurogenic mechanism which emphasized that enhance spontaneous contraction all induced by abnormal nerve fuction(for example:up-regulation of number and function of neuroreceptors)and its subsequent effects.②Myogenci mechanism:Brading and other research insisted that besides neurogenic dysfunction, myogenic factors such as increased excitability of detrusor smooth muscle, enhaced communication between detusor smooth cells、ganglionic cells and up-regulation of the number and function of "pacemaker cells".
As for myogenic mechanism of OAB, it is important for subsequent research to confirm whether pacemarker cells exist in bladder.ICCs(Interstitial cells of cajal) possesses different shape and function from smooth muscle cells.It has been accepted widely that as a pacemaker cell of gastrointestinal tract,ureter and other smooth muscle organs, spontaneous excitation of smooth muscle cells orginated from ICCs.With the help of immunofluorescence, ICCs(c-kit positive cells) were found distributed in bladder of guinea pig and human.ICCs, with Fusiform appearance, were showed to have a close relationship with smooth muscle cells and nerve ending and can generate spontaneous Ca~(2+) transients which suggested that ICCs may be the candidate of pacemaker cell of bladder. Subsequently,ICCs were found to drive spontaneous transient outward currents(STOCs) and Glivec, a specific c-kit inhibitot, were showed to significantly inbibit spontaneous action potentials(APs) of smooth muscle cells.These research data prompted that ICCs do have the ability of autodepolarization which confirmed the presence functionally and suggested that similiar gastrointestinal tract and ureter,ICCs may be the pacemaker cell in bladder.However, there are evidences points to the conclusion that APs can also be recorded in smooth muscle cells freshly isolated from bladder which prompted that smooth muscle cells may be another candidate of pacemaker cell of bladder spontaneous contraction .Then is ICCs or DSMCs the pacemaker cell of bladder? Research at tissue level should be taken to confirm since research data at single cell level are not sufficient to answer the question.
Release of calcium from intracellular stores, endoplasmic/sarcoplasmic reticulum (ER/SR), is one of the key signal transduction mechanisms that play a pivotal role in the regulation of numerous cellular functions. In smooth myocytes, Ca~(2+) release from intracellular Ca~(2+) stores to cytoplasm are controlled by ryanodine Ca~(2+) release receptors subtype 2 (RYR2), which can occur in form of spontaneous SR Ca~(2+) release events, or Ca~(2+) sparks, and Ca~(2+) release that is triggered by the influx of Ca~(2+) through sarcolemmal ion channels, often termed CICR.Intracellular Ca~(2+)-mediated excitation-contraction coupling in smooth muscle cells (DSMCs) is primarily controlled by the influx of extracellular Ca~(2+) and the mobilization of Ca~(2+) from intracellular stores. Ca~(2+) transients represent Ca~(2+) influx through voltage-dependent Ca~(2+) channels (VDCCs) during action potentials, the influx of extracellular Ca~(2+) produces smooth muscle constriction in part by stimulating Ca~(2+) release from the sarcoplasmic reticulum (SR) through Ca~(2+)-induced Ca~(2+) release (CICR).
Cyclic adenosine diphosphate ribose (cADPR) is a naturally occurring cyclic nucleotide and represents a novel class of endogenous Ca~(2+) messengers implicated in the regulation of the gating properties of ryanodine receptors (RyRs).In smooth muscle, cADPR can regulate Ca~(2+) transient by modulating Ca~(2+) release through RyR2 from SR. Alteration of gating properties of RyR2 induced by cADPR can regulate depolarization/repolarization and characteristic of Ca~(2+) transients of DSMCs by modulate STOCs(spontaneous transient outward current), STICs(spontaneous transient outward currents) and CICR. Howerver,the role and mechanism of cADPR regulation of Ca~(2+) release remain unclear and very controversial and investigating of the mechanism will help us to further comprehend the procedure that cADPR modulate Ca~(2+) transients of DSMCs.
Since there is a close relationship between Ca~(2+) transients and action potentials(APs) in smooth muscle tissue and cADPR is an important Ca~(2+) mobilizer which can modulate Ca~(2+) transients of DSMCs by regulating Ca~(2+) release from SR, we plan to do some works as following:First, immunofluorescence and immunofluorescence double staining protocol were used to obeserve the distribution of ICCs and its relationship with smooth muscle cells in the rat bladder;Second, spontaneous Ca~(2+) transients of ICCs and DSMCs were viewed in detrusor strips loaded with Fluo-4 AM by confocal microscopy, then amplitude and frequecy of spontanoues Ca~(2+) transients in ICCs and DSMCs were compared to initially investigate the function of ICCs;Third, a series of pharmacologic experiments were taken to explore the mechanism for generation and regulation of spontaneous Ca~(2+) transients in ICCs and DSMCs; finally, FKBP12.6 gene knockout mice were used to examine the effect and mechanism of cADPR on Ca~(2+) release in mouse bladder smooth muscle.
Materials and methods: Female SD rats of 2-3 months,weighing from 220-280g were used. Immunofluorescence(anti-cKit)and immunofluorescence double staining (anti-ckit and anti-myosin) protocol were used to obeserve the distribution of ICCs and its relationship with smooth muscle cells in the rat bladder. By referencing to methods estabilished by hashitani,we recorded spontaneous Ca~(2+) transients of ICCs and smooth muscle cells with confocal microscopy.Serosa and mucosa removed bladder strips were prepared and superfused with warmed physiological saline(PSS) to recover and maintain their activity. After spontaneous muscle movements of the muscle layers were visually detected, the tissues were loaded with the fluo-4 AM and then spontaneous Ca~(2+) transients of ICCs in the muscle layers were observed with confocal microscopy. Then L type Ca~(2+) channel blocker Nimodipine, T type Ca~(2+) channel blockers Nicl2 ,Ca~(2+) free and High Ca~(2+) physiological saline and several reagents which can interfere SR Ca~(2+) release were added to investigate the mechanism of generation of spontaneous Ca~(2+) transients in ICCs and DSMCs.
Then we sought to examine the effect and mechanism of cADPR on Ca~(2+) release in mouse bladder smooth muscle. We have used FKBP12.6 null mice to test directly if cADPR action on Ca~(2+) sparks is through FKBP12.6 disassociation from the RyR2 complex. Genetype of mice were tested by conducting a PCR (Polymerase Chain Reaction) on DNA samples taken from the mouse tail. Effects of cADPR on STOCs(spontaneous transient out currents) and Ca~(2+) sparks were recorded by patch clamp and confocal microscopy. Thapsigargin(A SERCA blocker) was used to detect whether SERCA activity is necessary for cADPR-induced increase in Ca~(2+) sparks.To further confirm that the effect of cADPR on Ca~(2+) spark properties is directly dependent on the dissociation of FKBP12.6 from the RyR2 complex, Western blotting analysis was performed on SR microsomes from mouse bladder smooth muscle. Previous studies demonstrated that the amount of FKBP12.6 bound to RYR2 can influence SR Ca~(2+) load. To determine whether cADPR affected SR Ca~(2+) content, caffeine (10 mM) was used to estimate SR Ca~(2+) load in myocytes of WT and FKBP12.6-null mice before and after cADPR treatment.
Results:
1. There are three categories ICCs in rat bladder strips, namely ICCs tracking smooth muscle boundary, ICCs between the bundles and ICCs in the bundles.There is a close relationship between ICCs and smooth muscle cells and neuro ending;
2. Properties of spontaneous Ca~(2+) transients recorded from DSMCs in detrusor strips
(1) Asynchronous Ca~(2+) transients were obeserved right after the ending of Fluo-4 loading protocol.Some 30 min after superfusion with dye free physiological saline, synchronous Ca~(2+) transients generated in smooth muscle bundles;
(2) Mostly, spontaneous Ca~(2+) transients of DSMCs originated along a boundary of each smooth muscle bundle and then spread to the other boundary.Some Ca~(2+) transients originated from the middle of the bundles and travelled to two boundaries.
(3) Delay of propagation can be observed along the transverse direction but not along the axial direction;
(4) Propagations of spontaneous Ca~(2+) transients between smooth muscle bundles were also observed by confocal laser scanning microscopy;
3. Frequency of spontaneous Ca~(2+) transients recorded from DSMCs were significantly faster than frequency of that recorded from ICCs which suggested that ICCs tracking smooth muscle bundles may not be the pacemaker cell of bladder spontaneous contraction;
4. Research data of subsequent pharmalogical experiments:
(1) Nimodipine can abolish spontaneous Ca~(2+) transients in DSMCs. Frequency but not amplitude of spontaneous Ca~(2+) transients in DSMCs was significantly reduced by Nicl2. No alteration induced by Nimodipine and Nicl2 in spontaneous Ca~(2+) transient were observed in ICCs.
(2) Ryanodien(RyR receptor antagonist),Caffeine(RyR receptor agonist),2-APB(IP3 receptor antagonist) and Thapsigargin(SERCA blocker) can significantly inhibite but can not abolish spontaneous Ca~(2+) transients of DSMCs.
(3) Contrary to findings in DSMCs, spontaneous Ca~(2+) transients of ICCs can be abolished by Ryanodien,Caffeine,2-APBand Thapsigargin.
(4) Ca~(2+) free physiological saline also are found can abolish spontaneous Ca~(2+) transients of ICCs.Frequncy of spontaneous Ca~(2+) transients of DSMCs can be increased significantly by high Ca~(2+) physiological solutions.
5. Mice that are from heterozygous (one wildtype allele and one knockout) knockout parents were tested for their genotype by PCR. Three genetype were found in mice:Wildtype(FKBP12.6 +/+),Knockout(FKBP12.6 -/-) and heterozygous (FKBP12.6 +/-).
6. On dialysis of 5μM cADPR into bladder smooth muscle cells via patch pipettes, both the frequency and amplitude of STOCs were significantly altered in wildtype cells.The frequency and amplitude of STOCs increased significantly in wildtype cells. In contrast to wildtype cells, the cells from FKBP12.6 null mice did not respond to cADPR stimulation.
7. Ca~(2+) sparks are due to the concerted opening of multiple RyRs and STOCs were generated by Ca~(2+) Sparks.Patch clamp and confocal microscopy combined study showed that on dialysis of wildtype cells with cADPR, both STOCs and Ca~(2+) sparks were markedly altered. In contrast, dialysis of FKBP12.6 knockout cells with cADPR resulted in a negligible change in the properties of STOCs and Ca~(2+) sparks.
8. After dialysis of cADPR, marked alterations were observed in WT cells but not in FKBP12.6 KO cells. Ca~(2+) spark frequency was increased significantly in wildtype but not in FKBP12.6 null cells. Similarly, on dialysis of wildtype cells with cADPR, peak Ca~(2+) (F/F0),FWHM increased remarkably; rise timeand half-time decay were both prolonged markedly. However, cADPR did not alter Ca~(2+) spark properties in FKBP12.6 knockout cells.
9. After dialysis of cADPR, Ca~(2+) spark frequency increased significantly and the alteration in Ca~(2+) spark frequency was not affected by thapsigargin. Similarly, increases in F/F0, FWHM, rise time and half-time decayinduced by cADPR were not markedly affected by thapsigargin.
10. The endogenous FKBP12.6 was released from SR microsomes by incubation with cADPR and practically all of the FKBP12.6 was bound to SR microsomes in the pellet.
11. It was notable that the FKBP12.6 protein deletion caused a reduction in Ca~(2+) content of SR in wildtype but not in FKBP12.6 null smooth muscle cells.
Conclusion:
1. Mechanism of spontaneous Ca~(2+) transients' propogation along the transverse direction may be different from that along the axial direction and spontaneous Ca~(2+) transients' propagate between smooth muscle bundles may have some relationship with etiology of detrusor instability;
2. Asynchronous Ca~(2+) transients were transformed to synchronous Ca~(2+) transients by superfusion with dye free physiological saline in smooth muscle bundles suggested pacemaker cell did exist in bladder and candidate of the pacemaker may include:①DSMCs at the boundary of smooth bundles;②ICCs tracking smooth muscle boundary and ICCs in the bundles. However some Ca~(2+) transients also were found originated from the middle of the bundles suggested that different distribution of pacemaker cells may existed in distinct muscle bundles;
3. Frequency of spontaneous Ca~(2+) transients recorded from DSMCs were significantly faster than that recorded from ICCs, which suggested that ICCs tracking smooth muscle bundles may not be the pacemaker cell of bladder spontaneous contraction. However, it is far from making a decision that ICCs tracking smooth muscle bundles are not the pacemake cell since we still have some technological problem(for example the limitation from focal length of confocal microscopy) and some ICCs tracking smooth muscle may have different functions. Besides, ICCs in the bundles may be another candidate of pacemaker cell of bladder sponteneous contraction;
4. DSMCs generated spontaneous Ca~(2+) transients via extracellular Ca~(2+) entry through L type Ca~(2+) channels and the spontanoue Ca~(2+) transients were partly supported by Ca~(2+) release from Ca~(2+) release from intracellular Ca~(2+) stores; T-type Ca~(2+) channels may contribute to the preceding depolarization to activate the L-type Ca~(2+) channels and maintain the resting potential of DSMCs and thus determine the action potential frequency;
5. spontaneous Ca~(2+) transients of ICCs rely on both Ca~(2+) release from intracellular Ca~(2+) stores and extracellular Ca~(2+) entry through non L type Ca~(2+) channels. Candidate of the non L type Ca~(2+) channels may include:①NCX(Na+/Ca~(2+) exchanger)②T type Ca~(2+) channels and③TRP channels;
6. cADPR significantly alters Ca~(2+) spark properties and Ca~(2+) content in SR and that the underlying mechanism of cADPR action is related to the dissociation of FKBP12.6 proteins from the RYR2 complex in mouse bladder smooth muscle.
膀胱逼尿肌是一种特殊的平滑肌组织,逼尿肌组织在受到神经支配的同时,是否存在类似心脏和胃肠道平滑肌的自发性兴奋,曾经是个认识不清的问题。我科对之进行了较系统的研究后发现:①离体条件下膀胱逼尿肌肌条可出现自发的兴奋性收缩;②离体膀胱逼尿肌条在多种神经递质拮抗剂“鸡尾酒”式的混合阻断下,仍然能产生收缩。以上研究结果及国外相关研究让我们认识到:逼尿肌组织具有自主产生兴奋的能力,这种自发性肌源性兴奋并不依赖于神经因素的作用而存在。
我们的实验研究还发现,在膀胱流出道梗阻和神经源性异常引起的逼尿肌不稳定(Detrusor instability,DI)时,这种肌源性的自发兴奋和收缩明显增强,表现为:不稳定逼尿肌肌条与正常逼尿肌肌条相比,自发性收缩的幅度和频率明显增加;同等张力负荷下不稳定逼尿肌肌条的自发性收缩频率较正常逼尿肌肌条明显增加。膀胱逼尿肌兴奋性增高亦常见于临床,如继发于神经源性膀胱功能障碍及膀胱出口梗阻时。这一异常现象的发生目前被归咎为两个基本的机制:①神经源性学说。这一学说居主导地位,以de Groat为代表,强调所有兴奋性改变均源于神经因素,或为神经因素的延续效应,主要是表现在神经受体的数量和功能的上调。②肌源性学说。以Brading为代表,认为兴奋性改变除神经因素作用外,尚有肌源性异常因素参与,包括逼尿肌肌细胞的兴奋性增高、细胞间信号传导功能的加强、逼尿肌细胞与神经节细胞的联系增加,以及膀胱内可能存在的起搏细胞功能数量及功能的上调等。对膀胱肌源性兴奋的机制进行研究将有望为相关膀胱功能障碍性疾病开创新的治疗策略提供理论基础。
在膀胱兴奋的肌源性学说这一理论中,膀胱内是否存在具有起搏功能的细胞至关重要,也一直为人们所重视。Cajal间质细胞(Interstitial cells of cajal,ICC)是一类与平滑肌细胞在形态及功能上均不相同细胞,业已证明这些细胞是胃肠道、输尿管等器官的起搏细胞,这些器官的平滑肌自发性兴奋均起源于其中ICCs细胞。McCloskey等及Shafik等采用c-kit特异性标记的方法,先后证实了在豚鼠和人的膀胱中存在ICCs细胞,这种细胞呈长梭形,在去极化时不能产生自发收缩,有别于正常的逼尿肌肌细胞,更为特异的是这种细胞c-kit表达呈阳性,它们主要沿肌束分布,并可产生钙活动,与神经和平滑肌细胞也有广泛的联系,极可能是起搏细胞或是兴奋调节细胞。后续ICCs细胞功能方面的研究发现,ICCs细胞具有自动除极的外向电流,c-kit的特异性阻断剂Glivec可显著抑制逼尿平滑肌束的自发性动作电位和兴奋收缩能力;提示ICCs细胞可能具备自动除极化,完成自动起搏的能力,这从功能学上肯定了ICCs细胞的存在以及其作为起搏细胞的可能性。但ICCs细胞是否是膀胱逼尿肌自发性兴奋的起搏细胞,目前尚无明确结论;开展膀胱逼尿肌组织中相关研究,特别对ICCs细胞和平滑肌细胞的自发性兴奋特征进行对比,将为阐明膀胱ICCs细胞是否是膀胱起搏细胞及其可能具有的功能提供重要的研究证据。
钙离子是细胞内信号转导重要的第二信使,在平滑肌细胞中,钙自发性释放入胞浆导致的钙火花(Ca~(2+) spark)及细胞外钙内流诱导内质网中钙释放(Ca~(2+) induced Ca~(2+) release, CICR)均是通过Ⅱ型Ryanodine受体(RyR2)完成的。细胞钙瞬变(Ca~(2+) transients)与动作电位的发生关系密切,是动作电位发生的重要信号。动作电位相关的平滑肌细胞膜去极化可致细胞膜上电压门控的钙离子通道开放,细胞外钙内流随后通过CICR作用诱导细胞内质网(sarcoplasmic reticulum,SR)中的钙释放入胞浆,导致细胞浆内钙离子浓度瞬间升高,引起细胞发生钙瞬变和平滑肌收缩。
环腺苷二磷酸核糖(Cyclic adenosine diphosphate ribose,cADPR)是细胞内烟酰胺腺嘌呤二核苷酸(NAD+)的代谢产物,是目前为止除钙离子外,平滑肌细胞内对细胞内质网上RyR2有调节作用的又一重要第二信使。以往的研究发现,cADPR可通过调控平滑肌细胞内质网RyR2开放对平滑肌细胞钙瞬变的发生及钙瞬变特征产生显著调节作用,其具体机制为:cADPR可通过影响细胞自发性瞬时外向电流(spontaneous transient outward currents,STOCs)、自发性瞬时内向电流(spontaneous transient outward currents,STICs)影响平滑肌细胞去极化,并可通过影响钙诱导的钙释放(CICR)影响平滑肌细胞细胞钙瞬变的幅度。但目前cADPR调节平滑肌细胞内质网钙释放的作用机制仍不清楚,研究结论还存在较大的矛盾。探讨cADPR调节平滑肌细胞内质网中钙释放这一cADPR调控细胞钙瞬变发生关键环节的机制,将为深入了解cADPR调控平滑肌细胞钙瞬变的过程提供实验依据。
考虑到细胞钙瞬变与细胞动作电位的发生密切相关,cADPR可通过影响细胞内质网中钙释放进而调控平滑肌钙瞬变的发生及其特征,本研究拟以细胞钙瞬变为观察指标,比较分析ICCs细胞和平滑肌细胞自发性钙瞬变的特征及发生机制;并以反映平滑肌细胞内钙释放的STOCs和钙火花(Ca~(2+) spark)为观察指标,通过利用FKBP12.6基因敲除小鼠,对cADPR调节平滑肌细胞内质网中钙释放的机制进行探讨。本研究将有助于我们深入对平滑肌细胞和ICCs细胞自发性钙瞬变特征、发生和调控的认识,并为阐明膀胱ICCs细胞的功能提供初步的研究证据。本研究拟从以下四个方面展开:
第一:利用免疫荧光单染及双染的方法,观察ICCs细胞在逼尿肌组织中的分布及与平滑肌细胞的关系,为后续平滑肌细胞和ICCs细胞自发性钙瞬变的检测提供参考;
第二:对膀胱逼尿肌组织铺片中的平滑肌细胞和相邻ICCs细胞自发性钙瞬变进行检测,比较分析两种细胞自发性钙瞬变的频率和幅度,初步探讨平滑肌相邻ICCs细胞可能的功能;
第三:检测细胞外钙内流及细胞钙库中钙释放干预因素对细胞自发性钙瞬变的影响,探讨细胞外钙内流及细胞内质网中钙释放入胞浆在两种细胞自发性钙瞬变发生的作用;
第四:对比野生型和FKBP12.6基因敲除小鼠中cADPR对膀胱平滑肌细胞STOCs、钙火花及细胞内质网总钙含量的影响,探讨cADPR调节平滑肌细胞内质网中钙释放这一cADPR调控细胞钙瞬变发生关键环节的机制,为深入了解cADPR调控平滑肌细胞钙瞬变的机制提供实验依据。
方法:本研究采用2-3月龄SD大鼠为研究对象。首先利用免疫荧光方法检测逼尿肌组织中ICCs细胞的分布及其与平滑肌细胞的关系。随后参照Hashitani等[18]的方法制作膀胱组织铺片,于记录Chamber底部Physiological saline生理液灌流保持肌条铺片活性。待肌条自发性收缩活动出现后,Fluo-4 AM负载肌条铺片,激光共聚焦显微镜观察铺片中平滑肌细胞和ICCs细胞自发性钙瞬变,随后分别观察L型、T型钙离子通道阻断剂Nimodipine、Nicl2,内质网IP3受体拮抗剂2-aminoethoxy diphenylborate (2-APB),内质网RyR受体拮抗剂Ryanodine,内质网RyR受体激动剂Caffeine,内质网钙泵抑制剂Thapsigargin及无钙、高钙生理液对平滑肌细胞和ICCs细胞自发性钙瞬变的影响,探讨平滑肌细胞和ICCs细胞自发性钙瞬变产生、调控的机制。
最后利用FKBP12.6基因敲除小鼠探讨cADPR调节膀胱平滑肌细胞内质网中钙释放的机制。通过PCR方法对敲除小鼠的基因表型进行鉴定。通过膜片钳记录cADPR对平滑肌细胞自发性瞬时外向电流(spontaneous transient out currents,STOCs)的影响,使用膜片钳和激光共聚焦显微镜共记录的方法,同步观察cADPR对平滑肌细胞STOCs和钙火花(Ca~(2+) spark)的影响。利用激光共聚焦显微镜观察cADPR对膀胱平滑肌细胞细胞钙火花特征的影响,并通过Thapsigargin预处理了解内质网钙泵是否参与cADPR调节平滑肌细胞中钙释放作用。利用Western blot实验,检测cADPR作用后,FKBP12.6从RyR2上释放入胞浆的情况。利用双Puff系统,通过瞬时使用10mM Caffeine,探讨cADPR对平滑肌细胞内质网中总钙含量的影响。
结果:
1. SD大鼠膀胱逼尿肌组织中存在ICCs细胞,ICCs细胞在逼尿肌肌束旁、肌束间和肌束内均有分布;ICCs细胞与平滑肌细胞、神经末梢在空间结构上紧密相邻;肌束旁和肌束间的ICCs细胞有时可连成一片,有可能成为相邻肌束之间联系的“桥梁”;
2.逼尿肌组织铺片中平滑肌细胞自发性钙瞬变的特征如下:
(1)逼尿肌组织铺片Fluo-4刚负载完成时,平滑肌束中平滑肌细胞自发性钙瞬变多不同步;热的生理液灌流20-30min后,平滑肌束中平滑肌细胞自发性钙瞬变趋于同步;
(2)平滑肌细胞钙瞬变多起源于肌束边缘,而后传递到肌束的另一侧;部分钙瞬变可起源于肌束中部,而后向肌束两侧传递;
(3)平滑肌细胞钙瞬变在肌束内纵向传递几乎无时间延迟,但其在肌束内横向传递有一定的时间延迟;
(4)观察到相邻的肌束间可通过肌束间细胞进行钙瞬变的传递。
3.成功同时记录到膀胱逼尿肌组织铺片中平滑肌细胞和肌束旁ICCs细胞的自发性钙瞬变,平滑肌细胞自发性钙瞬变频率相对较快,而肌束旁ICCs细胞的自发性钙瞬变频率相对较慢;
4.膀胱逼尿肌组织铺片中的药理实验研究发现:
(1) L型钙离子通道阻断剂Nimodipine能完全抑制平滑肌细胞的自发性钙瞬变,但对ICCs细胞的自发性钙瞬变无显著影响;T型钙离子通道阻断剂Nicl2可明显降低平滑肌细胞的自发性钙瞬变的频率,对平滑肌细胞钙瞬变的幅度及ICCs细胞的自发性钙瞬变无明显影响;
(2) Ryanodine,Caffeine,2-APB,和Thapsigargin均可对平滑肌细胞的自发性钙瞬变产生显著的抑制作用,但不能完全消除平滑肌细胞的自发性钙瞬变的发生;
(3) Ryanodine,Caffeine,2-APB,和Thapsigargin及无钙生理液均可完全抑制ICCs细胞的自发性钙瞬变,高钙生理液可显著增加ICCs细胞自发性钙瞬变的频率而降低其频率。
5.成功对FKBP12.6基因敲除小鼠进行了基因表型鉴定。经鉴定,基因敲除小鼠繁殖后,表现为三种基因表型:纯合子(FKBP12.6 -/-)、杂合子(FKBP12.6 +/-)和野生型(FKBP12.6 +/+);
6. cADPR可显著增大野生型小鼠膀胱平滑肌细胞的STOCs,对FKBP12.6基因敲除小鼠(纯和子)平滑肌细胞STOCs却无明显影响;
7.膜片钳和激光共聚焦显微镜共记录的研究结果发现,cADPR可显著增强野生型小鼠膀胱平滑肌细胞的STOCs及钙火花,但对FKBP12.6基因敲除小鼠平滑肌细胞STOCs及钙火花却无明显影响;
8. cADPR对野生型小鼠膀胱平滑肌细胞钙火花有显著影响,而对FKBP12.6基因敲除小鼠平滑肌细胞钙火花却无明显调节作用。具体表现为:cADPR可显著提高野生型小鼠膀胱平滑肌细胞钙火花的频率、幅度及FWHM距离,明显延长其上升时间和半数衰减时间;而cADPR对FKBP12.6基因敲除小鼠细胞钙火花的上述特征性指标无明显影响;
9.内质网钙泵抑制剂Thapsigargin对cADPR调节平滑肌细胞自发性钙释放的作用无明显影响;
10. Western blot实验证实,cADPR可使FKBP12.6从RyR2上脱落下来,释放入胞浆中;
11. cADPR可显著降低野生型小鼠膀胱平滑肌细胞内质网中的总钙含量,而对FKBP12.6基因敲除小鼠内质网中的总钙含量却无明显影响。
结论:
1.膀胱平滑肌自发性钙瞬变在肌束中纵向传递和横向传递的延迟不同可能来自传递机制的不同,而肌束间钙瞬变的传递增强可能参与DI的发生;
2.热生理液灌流使肌束中平滑肌细胞自发性钙瞬变趋于同步及钙瞬变多起源于肌束边缘提示:膀胱逼尿肌组织中存在起搏细胞的可能性很大,可能是膀胱起搏细胞的是:①肌束一侧的平滑肌细胞和②肌束旁或肌束内ICCs细胞;钙瞬变也可起源于肌束中部,提示不同部位的膀胱平滑肌组织起搏细胞的分布可能存在差异;
3.膀胱组织铺片中平滑肌细胞自发性钙瞬变频率明显快于肌束旁ICCs细胞,提示平滑肌细胞自发性钙瞬变起源于肌束旁ICCs细胞的可能性不大;考虑到目前肌束内ICCs细胞自发性钙瞬变尚不能进行检测,及目前技术手段对ICCs细胞自发性钙瞬变观察的限制,不排除肌束内和具有不同功能的肌束旁ICCs细胞是膀胱起搏细胞的可能性;
4.细胞外钙通过L型钙离子通道入胞在平滑肌细胞自发性钙瞬变发生中起主要作用,而细胞内钙库中的钙释放入胞浆可能起辅助作用;Ca~(2+)通过T型钙离子通道入胞则可影响细胞自发性钙瞬变的发生频率;
5.细胞外钙通过非L型钙离子通道入胞及胞内钙库中的钙释放均参与ICCs细胞自发性钙瞬变的发生;参与ICCs细胞自发性钙瞬变发生的细胞膜上的非L型钙离子通道可能是①钠钙交换体NCX、②T型钙离子通道和③TRP(瞬时受体势)离子通道中的多个通道;
6. cADPR调节平滑肌细胞内质网钙释放的机制是:使FKBP12.6从RyR2上脱落下来,导致RyR2通道开放明显增强,内质网中钙离子经RyR2通道释放入胞浆显著增加。
Bladder is a hollow muscular organ collects urine excreted by the kidneys prior to disposal by urination. The detrusor muscle is a layer of the urinary bladder wall made of smooth muscle fibers arranged in spiral, longitudinal, and circular bundles. As a speical smooth muscle tissue, the detrusor muscle is double controlled by splanchnic nerve and somatic nerves. Whether the detrusor muscle can generate spontaneous contraction like heart and gastrointestinal tract do was ever a mysterious question.Our previous research have demonstrated several interesting phenomenons:first, all the strips isolated from bladder exhibit spontaneous contraction activity under certain tension load, and the unstable strips will develop spontaneous contraction under little tension load; second, when under the same tension load, the frequency of unstable detrusor strips increases more significantly than that of normal detrusor; third, the spontaneous contraction is little affected by neural factors. These phenomenons indicated that the spontaneous contraction of detrusor strips may not be neurogenic, and the detrusor should have the ability of generating spontaneous excitability itself.
It is also notable that the detrusor muscle exhibited significant increased activity of spontaneous contraction in a urological condition termed as DI(Detrusor instability) induced by bladder outlet obstruction or abnormal nerve function. Compared with normal detrusor strips, Smaller tension load is sufficient to induced spontaneous contractions in unstable detrusor strips.When under the same tension load, the frequency of unstable detrusor strips increases more significantly than that of normal detrusor strips.The enhanced spontaneous contraction also were observed in patients with overactive bladder (OAB)who suffered nearogenic bladder dysfunction and partial bladder outlet obstruction.The etiology of OAB is unclear, and indeed there may be multiple possible causes.In present,two different mechanism were made to explanation cause and development of OAB.① neurogenic mechanism:de Groat is one of supporter of neurogenic mechanism which emphasized that enhance spontaneous contraction all induced by abnormal nerve fuction(for example:up-regulation of number and function of neuroreceptors)and its subsequent effects.②Myogenci mechanism:Brading and other research insisted that besides neurogenic dysfunction, myogenic factors such as increased excitability of detrusor smooth muscle, enhaced communication between detusor smooth cells、ganglionic cells and up-regulation of the number and function of "pacemaker cells".
As for myogenic mechanism of OAB, it is important for subsequent research to confirm whether pacemarker cells exist in bladder.ICCs(Interstitial cells of cajal) possesses different shape and function from smooth muscle cells.It has been accepted widely that as a pacemaker cell of gastrointestinal tract,ureter and other smooth muscle organs, spontaneous excitation of smooth muscle cells orginated from ICCs.With the help of immunofluorescence, ICCs(c-kit positive cells) were found distributed in bladder of guinea pig and human.ICCs, with Fusiform appearance, were showed to have a close relationship with smooth muscle cells and nerve ending and can generate spontaneous Ca~(2+) transients which suggested that ICCs may be the candidate of pacemaker cell of bladder. Subsequently,ICCs were found to drive spontaneous transient outward currents(STOCs) and Glivec, a specific c-kit inhibitot, were showed to significantly inbibit spontaneous action potentials(APs) of smooth muscle cells.These research data prompted that ICCs do have the ability of autodepolarization which confirmed the presence functionally and suggested that similiar gastrointestinal tract and ureter,ICCs may be the pacemaker cell in bladder.However, there are evidences points to the conclusion that APs can also be recorded in smooth muscle cells freshly isolated from bladder which prompted that smooth muscle cells may be another candidate of pacemaker cell of bladder spontaneous contraction .Then is ICCs or DSMCs the pacemaker cell of bladder? Research at tissue level should be taken to confirm since research data at single cell level are not sufficient to answer the question.
Release of calcium from intracellular stores, endoplasmic/sarcoplasmic reticulum (ER/SR), is one of the key signal transduction mechanisms that play a pivotal role in the regulation of numerous cellular functions. In smooth myocytes, Ca~(2+) release from intracellular Ca~(2+) stores to cytoplasm are controlled by ryanodine Ca~(2+) release receptors subtype 2 (RYR2), which can occur in form of spontaneous SR Ca~(2+) release events, or Ca~(2+) sparks, and Ca~(2+) release that is triggered by the influx of Ca~(2+) through sarcolemmal ion channels, often termed CICR.Intracellular Ca~(2+)-mediated excitation-contraction coupling in smooth muscle cells (DSMCs) is primarily controlled by the influx of extracellular Ca~(2+) and the mobilization of Ca~(2+) from intracellular stores. Ca~(2+) transients represent Ca~(2+) influx through voltage-dependent Ca~(2+) channels (VDCCs) during action potentials, the influx of extracellular Ca~(2+) produces smooth muscle constriction in part by stimulating Ca~(2+) release from the sarcoplasmic reticulum (SR) through Ca~(2+)-induced Ca~(2+) release (CICR).
Cyclic adenosine diphosphate ribose (cADPR) is a naturally occurring cyclic nucleotide and represents a novel class of endogenous Ca~(2+) messengers implicated in the regulation of the gating properties of ryanodine receptors (RyRs).In smooth muscle, cADPR can regulate Ca~(2+) transient by modulating Ca~(2+) release through RyR2 from SR. Alteration of gating properties of RyR2 induced by cADPR can regulate depolarization/repolarization and characteristic of Ca~(2+) transients of DSMCs by modulate STOCs(spontaneous transient outward current), STICs(spontaneous transient outward currents) and CICR. Howerver,the role and mechanism of cADPR regulation of Ca~(2+) release remain unclear and very controversial and investigating of the mechanism will help us to further comprehend the procedure that cADPR modulate Ca~(2+) transients of DSMCs.
Since there is a close relationship between Ca~(2+) transients and action potentials(APs) in smooth muscle tissue and cADPR is an important Ca~(2+) mobilizer which can modulate Ca~(2+) transients of DSMCs by regulating Ca~(2+) release from SR, we plan to do some works as following:First, immunofluorescence and immunofluorescence double staining protocol were used to obeserve the distribution of ICCs and its relationship with smooth muscle cells in the rat bladder;Second, spontaneous Ca~(2+) transients of ICCs and DSMCs were viewed in detrusor strips loaded with Fluo-4 AM by confocal microscopy, then amplitude and frequecy of spontanoues Ca~(2+) transients in ICCs and DSMCs were compared to initially investigate the function of ICCs;Third, a series of pharmacologic experiments were taken to explore the mechanism for generation and regulation of spontaneous Ca~(2+) transients in ICCs and DSMCs; finally, FKBP12.6 gene knockout mice were used to examine the effect and mechanism of cADPR on Ca~(2+) release in mouse bladder smooth muscle.
Materials and methods: Female SD rats of 2-3 months,weighing from 220-280g were used. Immunofluorescence(anti-cKit)and immunofluorescence double staining (anti-ckit and anti-myosin) protocol were used to obeserve the distribution of ICCs and its relationship with smooth muscle cells in the rat bladder. By referencing to methods estabilished by hashitani,we recorded spontaneous Ca~(2+) transients of ICCs and smooth muscle cells with confocal microscopy.Serosa and mucosa removed bladder strips were prepared and superfused with warmed physiological saline(PSS) to recover and maintain their activity. After spontaneous muscle movements of the muscle layers were visually detected, the tissues were loaded with the fluo-4 AM and then spontaneous Ca~(2+) transients of ICCs in the muscle layers were observed with confocal microscopy. Then L type Ca~(2+) channel blocker Nimodipine, T type Ca~(2+) channel blockers Nicl2 ,Ca~(2+) free and High Ca~(2+) physiological saline and several reagents which can interfere SR Ca~(2+) release were added to investigate the mechanism of generation of spontaneous Ca~(2+) transients in ICCs and DSMCs.
Then we sought to examine the effect and mechanism of cADPR on Ca~(2+) release in mouse bladder smooth muscle. We have used FKBP12.6 null mice to test directly if cADPR action on Ca~(2+) sparks is through FKBP12.6 disassociation from the RyR2 complex. Genetype of mice were tested by conducting a PCR (Polymerase Chain Reaction) on DNA samples taken from the mouse tail. Effects of cADPR on STOCs(spontaneous transient out currents) and Ca~(2+) sparks were recorded by patch clamp and confocal microscopy. Thapsigargin(A SERCA blocker) was used to detect whether SERCA activity is necessary for cADPR-induced increase in Ca~(2+) sparks.To further confirm that the effect of cADPR on Ca~(2+) spark properties is directly dependent on the dissociation of FKBP12.6 from the RyR2 complex, Western blotting analysis was performed on SR microsomes from mouse bladder smooth muscle. Previous studies demonstrated that the amount of FKBP12.6 bound to RYR2 can influence SR Ca~(2+) load. To determine whether cADPR affected SR Ca~(2+) content, caffeine (10 mM) was used to estimate SR Ca~(2+) load in myocytes of WT and FKBP12.6-null mice before and after cADPR treatment.
Results:
1. There are three categories ICCs in rat bladder strips, namely ICCs tracking smooth muscle boundary, ICCs between the bundles and ICCs in the bundles.There is a close relationship between ICCs and smooth muscle cells and neuro ending;
2. Properties of spontaneous Ca~(2+) transients recorded from DSMCs in detrusor strips
(1) Asynchronous Ca~(2+) transients were obeserved right after the ending of Fluo-4 loading protocol.Some 30 min after superfusion with dye free physiological saline, synchronous Ca~(2+) transients generated in smooth muscle bundles;
(2) Mostly, spontaneous Ca~(2+) transients of DSMCs originated along a boundary of each smooth muscle bundle and then spread to the other boundary.Some Ca~(2+) transients originated from the middle of the bundles and travelled to two boundaries.
(3) Delay of propagation can be observed along the transverse direction but not along the axial direction;
(4) Propagations of spontaneous Ca~(2+) transients between smooth muscle bundles were also observed by confocal laser scanning microscopy;
3. Frequency of spontaneous Ca~(2+) transients recorded from DSMCs were significantly faster than frequency of that recorded from ICCs which suggested that ICCs tracking smooth muscle bundles may not be the pacemaker cell of bladder spontaneous contraction;
4. Research data of subsequent pharmalogical experiments:
(1) Nimodipine can abolish spontaneous Ca~(2+) transients in DSMCs. Frequency but not amplitude of spontaneous Ca~(2+) transients in DSMCs was significantly reduced by Nicl2. No alteration induced by Nimodipine and Nicl2 in spontaneous Ca~(2+) transient were observed in ICCs.
(2) Ryanodien(RyR receptor antagonist),Caffeine(RyR receptor agonist),2-APB(IP3 receptor antagonist) and Thapsigargin(SERCA blocker) can significantly inhibite but can not abolish spontaneous Ca~(2+) transients of DSMCs.
(3) Contrary to findings in DSMCs, spontaneous Ca~(2+) transients of ICCs can be abolished by Ryanodien,Caffeine,2-APBand Thapsigargin.
(4) Ca~(2+) free physiological saline also are found can abolish spontaneous Ca~(2+) transients of ICCs.Frequncy of spontaneous Ca~(2+) transients of DSMCs can be increased significantly by high Ca~(2+) physiological solutions.
5. Mice that are from heterozygous (one wildtype allele and one knockout) knockout parents were tested for their genotype by PCR. Three genetype were found in mice:Wildtype(FKBP12.6 +/+),Knockout(FKBP12.6 -/-) and heterozygous (FKBP12.6 +/-).
6. On dialysis of 5μM cADPR into bladder smooth muscle cells via patch pipettes, both the frequency and amplitude of STOCs were significantly altered in wildtype cells.The frequency and amplitude of STOCs increased significantly in wildtype cells. In contrast to wildtype cells, the cells from FKBP12.6 null mice did not respond to cADPR stimulation.
7. Ca~(2+) sparks are due to the concerted opening of multiple RyRs and STOCs were generated by Ca~(2+) Sparks.Patch clamp and confocal microscopy combined study showed that on dialysis of wildtype cells with cADPR, both STOCs and Ca~(2+) sparks were markedly altered. In contrast, dialysis of FKBP12.6 knockout cells with cADPR resulted in a negligible change in the properties of STOCs and Ca~(2+) sparks.
8. After dialysis of cADPR, marked alterations were observed in WT cells but not in FKBP12.6 KO cells. Ca~(2+) spark frequency was increased significantly in wildtype but not in FKBP12.6 null cells. Similarly, on dialysis of wildtype cells with cADPR, peak Ca~(2+) (F/F0),FWHM increased remarkably; rise timeand half-time decay were both prolonged markedly. However, cADPR did not alter Ca~(2+) spark properties in FKBP12.6 knockout cells.
9. After dialysis of cADPR, Ca~(2+) spark frequency increased significantly and the alteration in Ca~(2+) spark frequency was not affected by thapsigargin. Similarly, increases in F/F0, FWHM, rise time and half-time decayinduced by cADPR were not markedly affected by thapsigargin.
10. The endogenous FKBP12.6 was released from SR microsomes by incubation with cADPR and practically all of the FKBP12.6 was bound to SR microsomes in the pellet.
11. It was notable that the FKBP12.6 protein deletion caused a reduction in Ca~(2+) content of SR in wildtype but not in FKBP12.6 null smooth muscle cells.
Conclusion:
1. Mechanism of spontaneous Ca~(2+) transients' propogation along the transverse direction may be different from that along the axial direction and spontaneous Ca~(2+) transients' propagate between smooth muscle bundles may have some relationship with etiology of detrusor instability;
2. Asynchronous Ca~(2+) transients were transformed to synchronous Ca~(2+) transients by superfusion with dye free physiological saline in smooth muscle bundles suggested pacemaker cell did exist in bladder and candidate of the pacemaker may include:①DSMCs at the boundary of smooth bundles;②ICCs tracking smooth muscle boundary and ICCs in the bundles. However some Ca~(2+) transients also were found originated from the middle of the bundles suggested that different distribution of pacemaker cells may existed in distinct muscle bundles;
3. Frequency of spontaneous Ca~(2+) transients recorded from DSMCs were significantly faster than that recorded from ICCs, which suggested that ICCs tracking smooth muscle bundles may not be the pacemaker cell of bladder spontaneous contraction. However, it is far from making a decision that ICCs tracking smooth muscle bundles are not the pacemake cell since we still have some technological problem(for example the limitation from focal length of confocal microscopy) and some ICCs tracking smooth muscle may have different functions. Besides, ICCs in the bundles may be another candidate of pacemaker cell of bladder sponteneous contraction;
4. DSMCs generated spontaneous Ca~(2+) transients via extracellular Ca~(2+) entry through L type Ca~(2+) channels and the spontanoue Ca~(2+) transients were partly supported by Ca~(2+) release from Ca~(2+) release from intracellular Ca~(2+) stores; T-type Ca~(2+) channels may contribute to the preceding depolarization to activate the L-type Ca~(2+) channels and maintain the resting potential of DSMCs and thus determine the action potential frequency;
5. spontaneous Ca~(2+) transients of ICCs rely on both Ca~(2+) release from intracellular Ca~(2+) stores and extracellular Ca~(2+) entry through non L type Ca~(2+) channels. Candidate of the non L type Ca~(2+) channels may include:①NCX(Na+/Ca~(2+) exchanger)②T type Ca~(2+) channels and③TRP channels;
6. cADPR significantly alters Ca~(2+) spark properties and Ca~(2+) content in SR and that the underlying mechanism of cADPR action is related to the dissociation of FKBP12.6 proteins from the RYR2 complex in mouse bladder smooth muscle.
引文
1.邱功阔,宋波,金锡御等.膀胱出口梗阻对逼尿肌兴奋性、收缩性及顺应性影响的实验研究.中华泌尿外科杂志,2000,21(7):421-423.
2. Li L, Jiang C, Song B, Yan J, Pan J.Altered expression of calcium-activated K and Cl channels in detrusor overactivity of rats with partial bladder outlet obstruction.BJU Int. 2008 Jun;101(12):1588-94..
3.卢根生,金锡御,宋波.逼尿肌不稳定超微结构改变的实验研究.解放军医学杂志,2002,27(3):219-220.
4. Jiang HH, Song B, Lu GS, etc. Loss of ryanodine receptor calcium-release channel expression associated with overactive urinary bladder smooth muscle contractions in a detrusor instability model. BJU Int, 2005,96 (3):428-33.
5. Li L, Qiu G, Hao P, Song B. Effect of partial bladder outlet obstruction on detrusor compliance, excitability and contractility in rats. Scand J Urol Nephrol, 2006, 40(4):293-9.
6. Meng E, Young JS, Brading AF.Spontaneous activity of mouse detrusor smooth muscle and the effects of the urothelium.Neurourol Urodyn. 2008;27(1):79-87.
7. de Groat WC. A neurologic basis for the overactive bladder.Urology,1997 Dec;50(6A Suppl):36-52; discussion 53-6.
8. Brading A F. A myogenic basis for the overactive bladder. Urology,1997,50(6A Supp l):57-67,68-73.
9. Sanders KM, Koh SD, Ward SM. Interstitial cells of cajal as pacemakers in the gastrointestinal tract. Annu Rev Physiol 2006; 68: 307-343.
10. Megan F. Klemm, Betty Exintaris and R. J. Lang. Identification of the cells underlying pacemaker activity in the guinea-pig upper urinary tract. The Journal of Physiology, 1999, 519(3): 867-884.
11. McCloskey, K. D. and A. M. Gurney.Kit positive cells in the guinea pig bladder.J Urol,2002,168(2):832-6.
12. Shafik A,El-Sibai O, Shafik A A, et al.Identification of interstitial cells of Cajal in human urinary bladder: concept of vesical pacemaker. Urology, 2004, 64 (4):809-813.
13. McCloskey KD. Characterization of outward currents in interstitial cells from theguinea p ig bladder.J Urol,2005,173(1):296-301.
14. Kubota Y, Biers SM, Kohri K, et al. Effects of imatinib mesylate(Glivec) as a c-kit tyrosine kinase inhibitor in the guinea pig urinary bladder.Neurourol Urodyn,2006, 25(3):205-210.
15. Biers SM, Reynard J M, Doore T, et al. The functional effects of a c-kit tyrosine inhibitor on guinea pig and human detrusor .BJU Int,2006,97(3):612-616.
16. Montgomery BS, Fry CH. The action potential and net membrane currents in isolated human detrusor smooth muscle cell.J Urol,1992,147,176-184.
17. Sui GP, Wu C, Fry CH. The electrophysiological properties of cultured and freshly isolated detrusor smooth muscle cells. J Urol. 2001,165(2):627-32.
18. Hashitani H, Fukuta H, Takano H, Klemm MF, Suzuki H.Origin and propagation of spontaneous excitation in smooth muscle of the guinea-pig urinary bladder.J Physiol. 2001 Jan 15;530(Pt 2):273-86.
19. Berridge MJ. Inositol trisphosphate and calcium signalling. Nature.1993;361:315–325.
20. Nelson, M.T., H. Cheng, M. Rubart, L.F. Santana, A.D. Bonev, H.J. Knot, and W.J. Lederer. Relaxation of arterial smooth muscle by calcium sparks. Science. 1995;270:633–637.
21. Lam E, Martin MM, Timerman AP, Sabers C, Fleischer S, Lukas T, Abraham RT, O'Keefe SJ, O'Neill EA, Wiederrecht GJ. A Novel FK506 Binding Protein Can Mediate the Immunosuppressive Effects of FK506 and Is Associated with the Cardiac Ryanodine Receptor.J Biol Chem. 1995 Nov 3;270(44):26511-22.
22. Xin HB, Rogers K, Qi Y, Kanematsu T, Fleischer S. Three amino acid residues determine selective binding of FK506-binding protein 12.6 to the cardiac ryanodine receptor. J. Biol. Chem. 1999;24- 274:15315-15319.
23. Ji G, Feldman ME, Greene KS, Sorrentino V, Xin HB, Kotlikoff MI. RYR2 Proteins Contribute to the Formation of Ca~(2+) Sparks in Smooth Muscle. J Gen Physiol. 2004 April; 123(4): 377–386.
24. Yano M, Kobayashi S, Kohno M, Doi M, Tokuhisa T, Okuda S, Suetsugu M, Hisaoka T, Obayashi M, Ohkusa T, Kohno M, Matsuzaki M. FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure.Circulation. 2003 Jan 28;107(3):477-84.
25. Huang F, Shan J, Reiken S, Wehrens XH, Marks AR.Analysis of calstabin2 (FKBP12.6) -ryanodine receptor interactions: rescue of heart failure by calstabin2 in mice. Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3456-61.
26. Xin HB, Rogers K, Qi Y, Kanematsu T, Fleischer S. Three amino acid residues determine selective binding of FK506-binding protein 12.6 to the cardiac ryanodine receptor. J. Biol. Chem. 1999;24- 274:15315-15319.
27. Xin HB, Senbonmatsu T, Cheng DS, Wang YX, Copello JA, Ji GJ, Collier ML, Deng KY, Jeyakumar LH, Magnuson MA, Inagami T, Kotlikoff MI, Fleischer S. Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy. Nature. 2002;416:334-338.
28. Prestle J, Janssen PM, Janssen AP, Zeitz O, Lehnart SE, Bruce L, Smith GL, Hasenfuss G. Overexpression of FK506-binding protein FKBP12.6 in cardiomyocytes reduces ryanodine receptor-mediated Ca(2+) leak from the sarcoplasmic reticulum and increases contractility.Circ Res. 2001 Feb 2;88(2):188-94.
29. Gómez AM, Schuster I, Fauconnier J, Prestle J, Hasenfuss G, Richard S. FKBP12.6 overexpression decreases Ca~(2+) spark amplitude but enhances [Ca~(2+)]i transient in rat cardiac myocytes. Am J Physiol Heart Circ Physiol. 2004 Nov;287(5):H1987-93.
30. Timerman AP, Onoue H, Xin HB, Barg S, Copello J, Wiederrecht G, Fleischer S. Selective binding of FKBP12.6 by the cardiac ryanodine receptor. J. Biol. Chem. 1996,271:20385–20391.
31. Noguchi N, Takasawa S, Nata K, Tohgo A, Kato I, Ikehata F, Yonekura H, Okamoto H.Cyclic ADP-ribose binds to FK506-binding protein 12.6 to release Ca~(2+) from islet microsomes. J Biol Chem. 1997;272:3133–3136.
32. Tang WX, Chen YF, Zou AP, Campbell WB, Li PL. Role of FKBP12.6 in cADPR-induced activation of reconstituted ryanodine receptors from arterial smooth muscle. Am J Physiol Heart Circ Physiol. 2002;282:H1304–H1310.
33. Wang YX, Zheng YM, Mei QB, Wang QS, Collier ML, Fleischer S, Xin HB, Kotlikoff MI.FKBP12.6 and cADPR regulation of Ca~(2+) release in smooth muscle cells. Am J Physiol Cell Physiol.2004;286:C538 -C546.
34. Fruen BR, Mickelson JR, Shomer NH, Velez P, Louis CF. Cyclic ADP-ribose does not affect cardiac or skeletal muscle ryanodine receptors. FEBS Lett. 1994 Sep 26;352(2): 123-6.
35. Guo X, Laflamme MA, Becker PL. Cyclic ADP-ribose does not regulate sarcoplasmicreticulum Ca~(2+) release in intact cardiac myocytes. Circ Res. 1996 Jul;79(1):147-51.
36. Copello JA, Qi Y, Jeyakumar LH, Ogunbunmi E, Fleischer S. Lack of effect of cADP-ribose and NAADP on the activity of skeletal muscle and heart ryanodine receptors. Cell Calcium. 2001 Oct;30(4):269-84.
37. Cheung DW.Modulation of spontaneous transient Ca~(2+)-activated K+ channel currents by cADP-ribose in vascular smooth muscle cells..Eur J Pharmacol. 2003 Jan 1;458(1-2):57-9.
38. McCarron JG, Chalmers S, Bradley KN, MacMillan D, Muir TC.Ca~(2+) microdomains in smooth muscle.Cell Calcium. 2006 Nov-Dec;40(5-6):461-93.
39. Lukyanenko V, Gy?rke I, Wiesner TF, Gy?rke S. Potentiation of Ca(2+) release by cADP-ribose in the heart is mediated by enhanced SR Ca(2+) uptake into the sarcoplasmic reticulum.Circ Res. 2001 Sep 28;89(7):614-22.
40. G. P. Sergeant, K. D. Thornbury, N. G. McHale, M. A. Hollywood. Interstitial cells of Cajal in the urethra. J. Cell. Mol. Med. Vol 10, No 2, 2006 pp. 280-291
41. Christensen J. A commentary on the morphological identification of interstitial cells of Cajal in the gut. J Auton Nerv Syst,1992;37:75-88
42. Shuttleworth CW, Xue C, Ward SM, de Vente J, Sanders KM. Immunohistochemical localization of 3', 5'-cyclicguanosine monophosphate in the canine proximal colon: responses to nitric oxide and electrical stimulation of enteric inhibitory neurons. Neuroscience, 1993;56:513-522
43. Young HM, McConalogue K, Furness JB, de Vente J. Nitric oxide targets in the guinea-pig intestine identified by induction of cyclic GMP immunoreactivity. Neuroscience, 1993;55:583-596
44. Xue C, Pollock J, Schmidt HHHW, Ward SM, Sanders KM. Expression of nitric oxide synthase by interstitial cells of the canine proximal colon. J Auton Nerv Syst, 1994;49:1-14
45. Komuro T, Zhou DS. Anti-c-kit protein immunoreactive cells corresponding to the interstitial cells of Cajal in the guinea-pig small intestine. J Auton Nerv Syst, 1996;61:169-174
45. Burns AJ, Herbert TM, Ward SM, Sanders KM. Interstitial cells of Cajal in the guinea-pig gastrointestinal tract as revealed by c-Kit immunohistochemistry. CellTissue Res, 1997;290:11-20
46. Wester T, Eriksson L, Olsson Y, Olsen L. Interstitial cells of Cajal in the human fetal small bowel as shown by c-kit immunohistochemistry. Gut, 1999;44:65-71
47. Kenny SE, Connell G, Woodward MN, Lloyd DA, Gosden CM, Edgar DH, Vaillant C. Ontogeny of interstitial cells of Cajal in the human intestine. J Pediatr Surg, 1999;34:1241-1247
48. Nakagawa T,Misawa H,Nakajima Y,et al.Absence of peristalsis in the ileum of W/W(V) mutant mice that are selectively deficient in myenteric interstitial cells of Cajia. J. Smooth Muscle Res.2005;41:141-151.
49. Yanagida H, Yanase H, Sanders KM, et al. Intestinal surgical resection disrupts electrical rhythmicity, neural responses, and interstitial cell networks. Gastroenterology. 2004;127(6):1748-1759.
50. Hashitani H, Brading AF, Suzuki H. Correlation between spontaneous electrical, calcium and mechanical activity in detrusor smooth muscle of the guinea-pig bladder. Br J Pharmacol,2004,141(1):183-93.
51. Kuo KH, Dai J, Seow CY, Lee CH, van Breemen C.Relationship between asynchronous Ca~(2+) waves and force development in intact smooth muscle bundles of the porcine trachea.Am J Physiol Lung Cell Mol Physiol. 2003 Dec;285(6):L1345-53.
52. Yanai Y, Hashitani H, Kubota Y, Sasaki S, Kohri K, Suzuki H.The role of Ni(2+)-sensitive T-type Ca(2+) channels in the regulation of spontaneous excitation in detrusor smooth muscles of the guinea-pig bladder.BJU Int. 2006 Jan;97(1):182-9.
53. Burdyga T, Shmygol A, Eisner DA, Wray S.A new technique for simultaneous and in situ measurements of Ca~(2+) signals in arteriolar smooth muscle and endothelial cells. Cell Calcium. 2003 Jul;34(1):27-33.
54.李龙坤,宋波.膀胱ICCs细胞与逼尿肌兴奋性关系研究现状.第三军医大学学报,2008,30(7):555-557.
55. McCloskey KD.Calcium currents in interstitial cells from the guinea-pig bladder.BJU Int. 2006 Jun;97(6):1338-43.
56. Heppner, T. J., A. D. Bonev, et al. (2005). "Elementary purinergic Ca~(2+) transients evoked by nerve stimulation in rat urinary bladder smooth muscle." J Physiol 564(Pt 1): 201-12.
57. Hashitani, H. , Bramich, N. J. & Hirst, G. D. S. (2000). Mechanisms of excitatory neuromuscular transmission in the guinea pig urinary bladder. Journal of Physiology 524, 565-579.
58. Li L, Jiang C, Hao P, Li W, Song C, Song B. Changes of gap junctional cell-cell communication in overactive detrusor in rats. Am J Physiol Cell Physiol. 2007,293(5):C1627-35.
59. Kim JC, Yoo JS, Park EY, Hong SH, Seo SI, Hwang TK.Muscarinic and purinergic receptor expression in the urothelium of rats with detrusor overactivity induced by bladder outlet obstruction.BJU Int. 2008 Feb;101(3):371-5.
60. Watanabe T, Omata S, Lee JZ, Constantinou CE.Comparative analysis of bladder wall compliance based on cystometry and biosensor measurements during the micturition cycle of the rat.Neurourol Urodyn. 1997;16(6):567-81.
61. Meng E, Young JS, Brading AF.Spontaneous activity of mouse detrusor smooth muscle and the effects of the urothelium.Neurourol Urodyn. 2008;27(1):79-87.
62. McCloskey KD, Anderson UA, Davidson RA, Bayguinov YR, Sanders KM, Ward SM.Comparison of mechanical and electrical activity and interstitial cells of Cajal in urinary bladders from wild-type and W/Wv mice.Br J Pharmacol. 2009 Jan; 156(2):273-83.
63. Brading AF, McCloskey KD.Mechanisms of Disease: specialized interstitial cells of the urinary tract--an assessment of current knowledge.Nat Clin Pract Urol. 2005 Nov;2(11):546-54.
64. Davidson RA, McCloskey KD.Morphology and localization of interstitial cells in the guinea pig bladder: structural relationships with smooth muscle and neurons.J Urol. 2005 Apr;173(4):1385-90.
65. Hashitani H, Hayase M, Suzuki H.Effects of imatinib mesylate on spontaneous electrical and mechanical activity in smooth muscle of the guinea-pig stomach.Br J Pharmacol. 2008 May;154(2):451-9. Epub 2008 Apr 14.
66. Lang, R. J. and M. F. Klemm. Interstitial cell of Cajal-like cells in the upper urinary tract[J]. J Cell Mol Med,2005,9(3): 543-56.
67.封建立,方强,丁砺蠡,宋波等.ICCs细胞在正常大鼠膀胱中的分布及对逼尿肌收缩的影响[J].第三军医大学学报,2008,30(7):558-560.
68. Johnston, L., C. Carson, et al. Cholinergic-induced Ca~(2+) signaling in interstitial cells of Cajal from the guinea pig bladder.Am J Physiol Renal Physiol, 2008, 294(3):F645-55.
69. Hashitani, H. and H. Suzuki.Properties of spontaneous Ca~(2+) transients recorded from interstitial cells of Cajal-like cells of the rabbit urethra in situ.J Physiol,2007,583(Pt 2):505-19.
70. Guangju Ji,Morris Feldman,Robert Doran,Warren Zipfel,and Michael I. Kotlikoff.Ca~(2+)-Induced Ca~(2+) Release through Localized Ca~(2+) Uncaging in Smooth Muscle. J Gen Physiol. 2006 March; 127(3):225-235.
71. Fritz N, Morel JL, Jeyakumar LH, Fleischer S, Allen PD, Mironneau J, Macrez N. RyR1-specific requirement for depolarization-induced Ca~(2+) sparks in urinary bladder smooth muscle.J Cell Sci. 2007 Nov 1;120(Pt 21):3784-91.
72. Lang RJ, Davidson ME & Exintaris B (2002). Pyeloureteralmotility and ureteral peristalsis. essential role of sensorynerves and endogenous prostaglandins. Exp Physiol 87,129–146.
73. Van Helden DF (1993). Pacemaker potentials in lymphaticsmooth muscle of the guinea-pig mesentery. J Physiol 471,465–479.
74. Bortoff A (1976). Myogenic control of intestinal motility.Physiol Rev 56, 418–434.
75. Axelsson J,Wahlstrom B, Johansson B & Jonsson O (1967).Influence of the ionic environment on spontaneous electricaland mechanical activity of the rat portal vein. Circ Res 21,609–618.
76. Bengtsson B, Chow EM & Marshall JM (1984). Activity ofcircular muscle of rat uterus at different times in pregnancy.Am J Physiol 246, C216–223.
77. Brading AF, Teramoto N, Dass N & McCoy R (2001).Morphological and physiological characteristics of urethralcircular and longitudinal smooth muscle. Scand J Urol Nephrol Suppl 207, 12-18.
78. Hayase M, Hashitani H, Kohri K, Suzuki H.Role of K(+) Channels in Regulating Spontaneous Activity in Detrusor Smooth Muscle In Situ in the Mouse Bladder.J Urol. 2009 Mar 18. [Epub ahead of print]
79. Hashitani H, Brading AF.Electrical properties of detrusor smooth muscles from the pig and human urinary bladder.Br J Pharmacol. 2003 Sep;140(1):146-58.
80. Domae K, Hashitani H, Suzuki H.Regional differences in the frequency of slow wavesin smooth muscle of the guinea-pig stomach.J Smooth Muscle Res. 2008 Dec;44(6):231-48.
81. van Helden DF, Imtiaz MS, Nurgaliyeva K, von der Weid P, Dosen PJ.Role of calcium stores and membrane voltage in the generation of slow wave action potentials in guinea-pig gastric pylorus.J Physiol. 2000 Apr 1;524 Pt 1:245-65.
82. Sergeant GP, Craven M, Hollywood MA, McHale NG, Thornbury KD.Spontaneous Ca~(2+) waves in rabbit corpus cavernosum: modulation by nitric oxide and cGMP.J Sex Med. 2009 Apr;6(4):958-66. Epub 2008 Dec 9.
83. Lang RJ, Tonta MA, Zoltkowski BZ, et al. Pyeloureteric peristalsis: role of atypical smooth muscle cells and interstitial cells of Cajal-like cells as pacemakers.J Physiol 2006;576(Pt 3):695-705.
84. Johnston L, Sergeant GP, Hollywood MA, et al. Calcium oscillations in interstitial cells of the rabbit urethra.J Physiol 2005;565(Pt 2):449-461
85. Sergeant GP, Hollywood MA, McCloskey KD, McHale NG, Thornbury KD. Role of IP(3) in modulation of spontaneous activity in pacemaker cells of rabbit urethra. Am J Physiol Cell Physiol. 2001; 280: C1349-56.
86. Sergeant GP, Bradley E, Thornbury KD, McHale NG, Hollywood MA.Role of mitochondria in modulation of spontaneous Ca~(2+) waves in freshly dispersed interstitial cells of Cajal from the rabbit urethra.J Physiol. 2008 Oct 1;586(Pt 19):4631-42.
87. Han C, Tavi P, Weckstr?m M.Role of the Na(+)-Ca(2+) exchanger as an alternative trigger of CICR in mammalian cardiac myocytes.Biophys J. 2002 Mar;82(3):1483-96.
88. Kitchens SA, Burch J, Creazzo TL.T-type Ca~(2+) current contribution to Ca~(2+)-induced Ca~(2+) release in developing myocardium.J Mol Cell Cardiol. 2003 May;35(5):515-23.
89. Walker RL, Koh SD, Sergeant GP, Sanders KM, Horowitz B. TRPC4 currents have properties similar to the pacemaker current in interstitial cells of Cajal. Am J Physiol Cell Physiol. 2002; 283: C1637-45.
90. Fritz N, Morel JL, Jeyakumar LH, Fleischer S, Allen PD, Mironneau J, Macrez N. RyR1-specific requirement for depolarization-induced Ca~(2+) sparks in urinary bladder smooth muscle.J Cell Sci. 2007 Nov 1;120(Pt 21):3784-91.
91. Mészáros LG, Bak J, Chu A. Cyclic ADP-ribose as an endogenous regulator of the non-skeletal type ryanodine receptor Ca~(2+) channel. Nature. 1993;364:76–79.
92. Clementi E, Riccio M, Sciorati C, Nistico G, and Meldolesi J. The type 2 ryanodine receptor of neurosecretory PC12 cells is activated by cyclic ADP-ribose. Role of the nitric oxide/cGMP pathway. J Biol Chem. 1996;271:17739-45.
93. Walsh JV Jr, Singer JJ.Ca++ activated K+ channels in vertebrate smooth muscle cells. Cell Calcium. 1983;4:321-330.
94. Trieschmann U, Isenberg G. Ca~(2+) activated K+ channels contribute to the resting potential of vascular myocytes. Ca~(2+) sensitivity is increased by intracellular Mg2+ ions. Pflugers Arch. 1989;414:S183–S184.
95. Wang, Y.X., B.K. Fleischmann, and M.I. Kotlikoff. Modulation of maxi-K+ channels by voltage-dependent Ca~(2+) channels and methacholine in single airway myocytes. Am. J. Physiol. 1997;272:C1151-C1159.
96. Su Z, Sugishita K, Li F, Ritter M, Barry WH. Effects of FK506 on [Ca~(2+)]i differ in mouse and rabbit ventricular myocytes. J Pharmacol Exp Ther. 2003 Jan;304 (1):334-41.
97. Iino S, Cui Y, Galione A, Terrar DA. Actions of cADP-ribose and its antagonists on contraction in guinea pig isolated ventricular myocytes. Influence of temperature.Circ Res. 1997 Nov;81(5):879-84.
98. Lehnart SE, Terrenoire C, Reiken S, Wehrens XH, Song LS, Tillman EJ, Mancarella S, Coromilas J, Lederer WJ, Kass RS, Marks AR. Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias.Proc Natl Acad Sci U S A. 2006 May 16;103 (20):7906-10.
99. Galione A, Lee HC, Busa WB. Ca~(2+)-induced Ca~(2+) release in sea urchin egg homogenates: modulation by cyclic ADP-ribose.Science. 1991; 253:1143– 1146.
100. Li PL, Tang WX, Valdivia HH, Zou AP, Campbell WB.cADP-ribose activates reconstituted ryanodine receptors fromcoronary arterial smooth muscle. Am J Physiol Heart Circ Physiol. 2001;280:H208–H215.
101. Perez, GJ, Bonev, AD, Patlak, JB and Nelson, MT. Functional coupling of ryanodine receptors to KCa channels in smooth muscle cells from rat cerebral arteries. J. Gen. Physiol.,1999,113:229- 238.
102. Xiao RP, Valdivia HH, Bogdanov K, Valdivia C, Lakatta EG, and Cheng H. The immunophilin FK506-binding protein modulates Ca~(2+) release channel closure in ratheart. J Physiol.1997;500: 343-354.
103. McCall E, Li L, Satoh H, Shannon TR, Blatter LA, Bers DM. Effects of FK-506 on contraction and Ca~(2+) transients in rat cardiac myocytes.Circ Res. 1996 Dec;79(6):1110-21.
104. Loughrey CM, Seidler T, Miller SL, Prestle J, MacEachern KE, Reynolds DF, Hasenfuss G, Smith GL. Over-expression of FK506-binding protein FKBP12.6 alters excitation-contraction coupling in adult rabbit cardiomyocytes.J Physiol. 2004 May 1;556(Pt 3):919-34.
105. Morita K, Kitayama T, Kitayama S and Dohi T.Cyclic ADP-ribose requires FK506-binding protein to regulate intracellular Ca~(2+) dynamics and catecholamine release in acetylcholine-stimulated bovine adrenal chromaffin cells.J Pharmacol Sci. 2006 May; 101 (1):40-51.
106. Prakash YS, Kannan M, Walseth TF and Sieck GC. cADPR ribose and [Ca~(2+)]i regulation in rat cardiac myocytes. Am J Physiol Heart Circ Physiol. 2000; 279:1482-1489.
107. Brillantes AB, Ondrias K, Scott A, Kobrinsky E, OndriasováE, Moschella MC, J ayaraman T, Landers M, Ehrlich BE, Marks AR. Stabilization of calcium release channel (ryanodine receptor) function by FK506-binding protein.Cell. 1994 May 20;77(4):513-23.
108. Cui Y, Galione A, Terrar DA.Effects of photoreleased cADP-ribose on calcium transients and calcium sparks in myocytes isolated from guinea-pig and rat ventricle.Biochem J. 1999 Sep 1;342 ( Pt 2):269-73.
109. Iino S, Cui Y, Galione A, Terrar DA. Actions of cADP-ribose and its antagonists on contraction in guinea pig isolated ventricular myocytes. Influence of temperature.Circ Res. 1997 Nov;81(5):879-84.
110. Rakovic S, Galione A, Ashamu GA,et al.A specific cyclic ADP-ribose antagonist inhibits cardiac excitation-contraction coupling.Curr Biol. 1996 Aug 1;6(8):989-96.
111. ZhuGe R, Fogarty KE, Tuft RA, Lifshitz LM, Sayar K, Walsh JV Jr.Dynamics of signaling between Ca(2+) sparks and Ca(2+)- activated K(+) channels studied with a novel image-based method for direct intracellular measurement of ryanodine receptor Ca(2+) current.J Gen Physiol. 2000 Dec;116(6):845-64.
112. Y.X. Wang, Y.M. Zheng, Q.B. Mei, et al., FKBP12,6 and cADPR regulation of Ca~(2+) release in smooth muscle cells, Am. J. Physiol.Cell Physiol. 286 (2004) C538–C546.
113. Y.S. Prakash, M.S. Kannan, T.F. Walseth, G.C. Sieck, Role of cyclic ADP-ribose in the regulation of [Ca~(2+)]i in porcine tracheal smooth muscle, Am. J. Physiol. 274 (1998) C1653–C1660.
114. A.J. Lokuta, A. Darszon, C. Beltran, H.H. Valdivia, Detection and functional characterization of ryanodine receptors from sea urchin eggs, J. Physiol. 510 (1998) 155–164.
115. C.F. Perez, J.J. Marengo, R. Bull, C. Hidalgo, Cyclic ADP-ribose activates caffeine-sensitive calcium channels from sea urchin egg microsomes, Am. J. Physiol. 274 (1998) C430–C439.
116. L.G. Meszaros, J. Bak, A. Chu, Cyclic ADP-ribose as an endogenous regulator of the non-skeletal type ryanodine receptor Ca~(2+) channel,Nature 364 (1993) 76–79.
117. R. Sitsapesan, S.J. McGarry, A.J. Williams, Cyclic ADP-ribose, the ryanodine receptor and Ca~(2+) release, Trends Pharmacol. Sci. 16(1995) 386–391.
118. B.R. Fruen, J.R. Mickelson, N.H. Shomer, P.Velez, C.F. Louis, Cyclic ADP-ribose does not affect cardiac or skeletal muscle ryanodine receptors, FEBS Lett. 352 (1994) 123–126.
119. A.M. Evans, C.N.Wyatt, N.P. Kinnear, J.H. Clark, E.A. Blanco, Pyridine nucleotides and calcium signalling in arterial smooth muscle:from cell physiology to pharmacology, Pharmacol. Ther. 107 (2005)286–313.
120. J.M. Thomas, R. Masgrau, G.C. Churchill, A. Galione, Pharmacological characterization of the putative cADP-ribose receptor, Biochem.J. 359 (2001) 451–457.
121. T.F. Walseth, R. Aarhus, J.A. Kerr, H.C. Lee, Identification of cyclic ADP-ribose-binding proteins by photoaffinity labeling, J. Biol. Chem.268 (1993) 26686–26691.
122. C. Franzini-Armstrong, F. Protasi, Ryanodine receptors of striated muscles: a complex channel capable of multiple interactions, Physiol.Rev. 77 (1997) 699-729.
123. M.G. Chelu, C.I. Danila, C.P. Gilman, S.L. Hamilton, Regulation of ryanodine receptors by FK506 binding proteins, Trends Cardiovasc.Med. 14 (2004) 227–234.
124. N. Noguchi, S. Takasawa, K. Nata, et al., Cyclic ADP-ribose binds to FK506-bindingprotein 12.6 to release Ca~(2+) from islet microsomes,J. Biol. Chem. 272 (1997) 3133–3136.
125. K.N. Bradley, S. Currie, D. MacMillan, T.C. Muir, J.G. McCarron,Cyclic ADP-ribose increases Ca~(2+) removal in smooth muscle, J. Cell Sci. 116 (2003) 4291–4306.
126. J.A. Copello, Y. Qi, L.H. Jeyakumar, E. Ogunbunmi, S. Fleischer,Lack of effect of cADP-ribose and NAADP on the activity of skeletal muscle and heart ryanodine receptors, Cell Calcium 30 (2001)269-284.
127. G. Bultynck, P. De Smet, D. Rossi, et al., Characterization and mapping of the 12 kDa FK506-binding protein (FKBP12)—binding site on different isoforms of the ryanodine receptor and of the inositol 1,4,5-trisphosphate receptor, Biochem. J. 354 (2001) 413–422.
128. W.X. Tang, Y.F. Chen, A.P. Zou, W.B. Campbell, P.L. Li, Role of FKBP12.6 in cADPR-induced activation of reconstituted ryanodine receptors from arterial smooth muscle, Am. J. Physiol. Heart Circ.Physiol. 282 (2002) H1304–H1310.
129. G. Bultynck, D. Rossi, G. Callewaert, et al., The conserved sites for the FK506-binding proteins in ryanodine receptors and inositol 1,4,5-trisphosphate receptors are structurally and functionally different, J.Biol. Chem. 276 (2001) 47715–47724.
130. E.D. Moore, T. Voigt, Y.M. Kobayashi, et al., Organization of Ca~(2+)release units in excitable smooth muscle of the guinea-pig urinarybladder, Biophys. J. 87 (2004) 1836–1847.
131. H.J. Schatzmann, The calcium pump of the surface membrane and ofthe sarcoplasmic reticulum, Annu. Rev. Physiol. 51 (1989) 473–485.
132. Liu HN, Ohya S, Furuzono S, Wang J, Imaizumi Y, Nakayama S. Co-contribution of IP3R and Ca~(2+) influx pathways to pacemaker Ca~(2+) activity in stomach ICC.J Biol Rhythms. 2005 Feb;20(1):15-26.
1. Cajal.S.R. Sur les ganglions et plexus nerveux de I'intestin. Compt Rend Soc Biol, 1893, 45:217-233.
2. Rogers DC, Burnstock G. The intersitial cell and its place in the concept of the autonomic ground plexus. J Comp Neurol. 1966,126, 255-284
3. Imaizumi M, Hama K. An electromicroscopic study on the interstitial cells of the gizzard in the love bird (Uronloncha domestica). Z Zellforsch Mikrosk Anat.1969, 97, 351-357.
4. Thuneberg L. Interstitial cells of Cajal: intestinal pacemaker cells? Adv Anat Embryol Cell Biol, 1982, 71:1-130.
5. Faussone-Pellegrini MS, Thuneberg L. Guide to the identification of interstitial cells of Cajal. Microsc Res Tech, 1999, 47(4):248-266.
6. Hanani M, Freund HR. Interstitial cells of Cajal--their role in pacing and signal transmission in the digestive system. Acta Physiol Scand, 2000, 170(3): 177-190.
7. Komuro T. Comparative morphology of interstitial cells of Cajal: ultrastructural characterization. Microsc Res Tech, 1999;47:267-285
8. Faussone-Pellegrini MS, Thuneberg L. Guide to the identification of interstitial cells of Cajal. Microsc Res Tech, 1999;47:248-266
9. Komuro T, Seki K, Horiguchi K. Ultrastructural characterization of the interstitial cells of Cajal. Arch Histol Cytol, 1999;62:295-316
10. Komuro T, Seki K, Horiguchi K. Ultrastructural characterization of the interstitial cells of Cajal. Arch Histol Cytol 1999; 62: 295-316
11. Kobayashi S. The structure of the autonomic and apparatus in the guinea-pig small intestine and the problem of the interstitial cells of Cajal. Acta Med Biol , 1990;38:103-127
12. Christensen J. A commentary on the morphological identification of interstitial cells of Cajal in the gut. J Auton Nerv Syst,1992;37:75-88
13. Zhou DS, Komuro T. Ultrastructure of the zinc iodide-osmic acid staining cells in guinea pig small intestine. J Anat,1995;187:481-485
14.童卫东,张胜本,张连阳,蔡文琴,杜文华,牟江洪.大鼠结肠肌间神经丛Cajal间质细胞的形态.解剖学杂志,1999;22:316-318
15. Ward SM, Burke EP, and Sanders KM.Use of rhodamine-123 to label and lesion interstitial cells of Cajal in canine colonic circular muscle. Anat Embry, 1990;182:215-224
16. Xue C, Ward SM, Shuttleworth CW, Sanders KM. Identification of interstitial cells in canine proximal colon using NADH diaphorase histochemistry. Histochemistry, 1993;99:373-384
17. Anderson CR, Edwards SL. Subunit of cholera toxin labels interstitial cells of Cajal in the gut of rat and mouse. Histochemistry, 1993;100:457-464
18. Hanani M, Louzon V, Miller SM, Faussone-Pellegrini MS. Visualization of interstitial cells of Cajal in the mouse colon by vital staining. Cell Tissue Res, 1998;292: 275-282
19. Hanani M, Belzer V, Rich A, Faussone Faussone-Pellegrini SM. Visualization of interstitial cells of Cajal in living, intact tissues. Microsc Res, 1999;47:336-343
20. Shuttleworth CW, Xue C, Ward SM, de Vente J, Sanders KM. Immunohistochemical localization of 3', 5'-cyclic guanosine monophosphate in the canine proximal colon: responses to nitric oxide and electrical stimulation of enteric inhibitory neurons. Neuroscience, 1993;56:513-522
21. Young HM, McConalogue K, Furness JB, de Vente J. Nitric oxide targets in theguinea-pig intestine identified by induction of cyclic GMP immunoreactivity. Neuroscience, 1993;55:583-596
22. Xue C, Pollock J, Schmidt HHHW, Ward SM, Sanders KM. Expression of nitric oxide synthase by interstitial cells of the canine proximal colon. J Auton Nerv Syst, 1994;49:1-14
23. Christensen J. A commentary on the morphological identification of interstitial cells of Cajal in the gut. J Auton Nerv Syst,1992;37:75-88
24. Shuttleworth CW, Xue C, Ward SM, de Vente J, Sanders KM. Immunohistochemical localization of 3', 5'-cyclicguanosine monophosphate in the canine proximal colon: responses to nitric oxide and electrical stimulation of enteric inhibitory neurons. Neuroscience, 1993;56:513-522
25. Young HM, McConalogue K, Furness JB, de Vente J. Nitric oxide targets in the guinea-pig intestine identified by induction of cyclic GMP immunoreactivity. Neuroscience, 1993;55:583-596
26. Xue C, Pollock J, Schmidt HHHW, Ward SM, Sanders KM. Expression of nitric oxide synthase by interstitial cells of the canine proximal colon. J Auton Nerv Syst, 1994;49:1-14
27. Komuro T, Zhou DS. Anti-c-kit protein immunoreactive cells corresponding to the interstitial cells of Cajal in the guinea-pig small intestine. J Auton Nerv Syst, 1996;61:169-174
28. Burns AJ, Herbert TM, Ward SM, Sanders KM. Interstitial cells of Cajal in the guinea-pig gastrointestinal tract as revealed by c-Kit immunohistochemistry. Cell Tissue Res, 1997;290:11-20
29. Wester T, Eriksson L, Olsson Y, Olsen L. Interstitial cells of Cajal in the human fetal small bowel as shown by c-kit immunohistochemistry. Gut, 1999;44:65-71
30. Kenny SE, Connell G, Woodward MN, Lloyd DA, Gosden CM, Edgar DH, Vaillant C. Ontogeny of interstitial cells of Cajal in the human intestine. J Pediatr Surg, 1999;34:1241-1247
31. Nakagawa T,Misawa H,Nakajima Y,et al.Absence of peristalsis in the ileum of W/W(V) mutant mice that are selectively deficient in myenteric interstitial cells of Cajia. J. Smooth Muscle Res.2005;41:141-151.
32. Sanders KM, Ward SM.Interstitial cells of Cajal: a new perspective on smooth musclefunction.J Physiol. 20061;576(Pt 3):721-726.
33. Sanders KM, Ward SM. Kit mutants and gastrointestinal physiology.J Physiol. 2007;578(Pt 1):33-42.
34. Park SJ,Mckay CM, Zhu Y,Huizinga JD.Volume-activated chloride currents in interstitial cells of Cajal. Am. J. Physiol Gastrointest. Liver Physiol.2005; 289: 791-797
35. Yanagida H, Yanase H, Sanders KM, et al. Intestinal surgical resection disrupts electrical rhythmicity, neural responses, and interstitial cell networks. Gastroenterology. 2004;127(6):1748-1759.
36. Ward SM, Dixon RE, de Faoite A, et al.Voltage-dependent calcium entry underlies propagation of slow waves in canine gastric antrum. J Physiol. 2004;561(Pt 3):793-810.
37. Forrest AS, Ord?g T, Sanders KM.Neural regulation of slow-wave frequency in the murine gastric antrum. Am J Physiol Gastrointest Liver Physiol. 2006; 290 (3):G486-495
38. Megan F. Klemm, Betty Exintaris and R. J. Lang. Identification of the cells underlying pacemaker activity in the guinea-pig upper urinary tract. The Journal of Physiology, 1999, 519(3): 867-884.
39. Lang RJ, Takano H, Davidson ME, et al. Characterization of the spontaneous electrical and contractile activity of smooth muscle cells in the rat upper urinary tract. The Journal of urology, 2001, 166(1):329-334.
40. Pezzone MA., Simon C. Watkins, Sean M. Alber et al. Identification of c-kit-positive cells in the mouse ureter: the interstitial cells of Cajal of the urinary tract. Am J Physiol Renal Physiolv, 2003, 284(5):925-929.
41. Metzger R, Schuster T, Till H, et al. Cajal-like cells in the human upper urinary tract. The journal of urology, 2004,172(2) :769-772.
42. van der AA, F, Roskams T, Blyweert W,et al. Identification fo kit positive cells in the human urinary tract. The journal of urology, 2004, 171(6):2492-2496.
43. Solari V, Piotrowska A, Piaseczna P. Altered Expression of Interstitial Cells of Cajal in Congenital Ureteropelvic Junction Obstruction. The journal of urology, 2003,170(6): 2420-2422.
44. Smet PJ, Jonavicius J, Marshall VR,et,al. Distribution of nitric oxidesynthase-immunoreactive nerves and identification of the cellular targets of nitric oxide in guinea-pig and human urinary bladder by cGMP immunohistochemistry. Neuroscience, 1996, 71(2):337-48.
45. Karen D. McCloskey, Alison M. Gurney Kit positive cells in the guinea pig bladder. J Urol, 2002, 168(2):832-836.
46. 46.A. Shafik Study of the electromechanical activity of the urinary bladder: an experimental study. World J Urol (1994) 12:316-318
47. Piaseczna Piotrowska A, Rolle U, Solari V, et al. Interstitial cells of Cajal in the human normal urinary bladder and in the bladder of patients with megacystis- microcolon intestinal hypoperistalsis syndrome. BJU Int, 2004, 94:143-146.
48. Hashitani H, Fukuta H, Takano H, et al. Origin and propagation of spontaneous excitation in smooth muscle of the guinea-pig urinary bladder. J Physiol, 2001, 530(2):273-286.
49. Piaseczna Piotrowska A, Rolle U, Solari V, et al. Interstitial cells of Cajal in the human normal urinary bladder and in the bladder of patients with megacystis-microcolon intestinal hypoperistalsis syndrome. BJU Int, 2004, 94:143- 146.
50.沈文浩,李为兵,熊恩庆,卢根生,宋波。胃肠道起搏细胞在豚鼠泌尿道分布研究。第三军医大学学报,2006,28(2):172-173.
51. Sergeant GP, Hollywood MA, McCloskey KD, et al. Specialised pacemaking cells in the rabbit urethra. J Physiol, 2000, 526 Pt 2:359 - 366.
52. Van der AA, F, Roskams T, Blyweert W, et al. Identification of kit positive cells in the human urinary tract. The journal of urology, 2004, 171(6):2492-2496.
53. Exintaris B, KlemmMF, Lang RJ. Spontaneous slow wave and contractile activity of the guinea pig prostate. J Urol, 2002, 168(1):315 - 322.
54. Frank Van der AA, Tania Roskams, Wim Blyweert, etal.Interstitial Cells in the Human Prostate: A NewTherapeuticTarget? TheProstate, 2003, 56:250-255.
55. Hikaru Hashitani, Hikaru Suzuki. Identification of interstitial cells of Cajal in corporal tissues of the guinea-pig penis. British Journal of Pharmacology, 2004, 141: 199-204.
56. Sergeant GP, Hollywood MA, McHale NG, Thornbury KD.Ca~(2+) signalling in urethral interstitial cells of Cajal.J Physiol. 2006 Nov 1;576(Pt 3):715-20.
57. Wang XY, Sanders KM, Ward SM. Intimate relationship between interstitial cells of cajal and enteric nerves in the guinea-pig small intestine. Cell Tissue Res 1999; 295: 247-256.
1. Clapper, D. L., Walseth, T. F., Dargie, P. J., & Lee, H. C. (1987). Pyridine nucleotide metabolites stimulate calcium release from sea urchin egg microsomes desensitized to inositol trisphosphate. J Biol Chem 262,9561-9568.
2. Aarhus, R., Graeff, R. M., Dickey, D. M., Walseth, T. F., & Lee, H. C.ADP-ribosyl cyclase and CD38 catalyze the synthesis of a calcium-mobilizing metabolite from NADP. J Biol Chem 270,30327-30333.
3. Galione, A. (1993). Cyclic ADP-ribose: a new way to control calcium.Science 259, 325– 326.
4. Lee, H. C. (1993). Potentiation of calcium- and caffeine-induced calcium release by cyclic ADP-ribose. J Biol Chem 268, 293–299.
5. Yu, J. Z., Zhang, D. X., Zou, A. P., Campbell, W. B., & Li, P. L. (2000).Nitric oxide inhibits Ca(2+) mobilization through cADP-ribose signaling in coronary arterial smooth muscle cells. Am J Physiol Heart Circ Physiol 279, H873-H881.
6. Lee, H. C., Walseth, T. F., Bratt, G. T., Hayes, R. N., & Clapper, D. L.(1989). Structural determination of a cyclic metabolite of NAD+ with intracellular Ca~(2+)-mobilizing activity. J Biol Chem 264, 1608–1615.
7. Lee, H. C., & Aarhus, R. (1991). ADP-ribosyl cyclase: an enzyme that cyclizes NAD+ into a calcium-mobilizing metabolite. Cell Regul 2,203– 209.
8. Rusinko, N., & Lee, H. C. (1989). Widespread occurrence in animal tissues of an enzyme catalyzing the conversion of NAD+ into a cyclic N. Bai et al. / Pharmacology & Therapeutics 105 (2005) 189–207 205 metabolite with intracellular Ca~(2+)-mobilizing activity. J Biol Chem 264,11725-11731.
9. Lee, H. C. (1996). Modulator and messenger functions of cyclic ADPribose in calcium signaling. Recent Prog Horm Res 51, 355–388.
10. Mitsui-Saito, M., Kato, I., Takasawa, S., Okamoto, H., & Yanagisawa, T.(2003). CD38 gene disruption inhibits the contraction induced byalpha-adrenoceptor stimulation in mouse aorta. J Vet Med Sci 65,1325-1330.
11. Cheung, D. W. (2003). Modulation of spontaneous transient Ca~(2+)-activated K+ channel currents by cADP-ribose in vascular smooth muscle cells.Eur J Pharmacol 458, 57– 59.
12. Y.X. Wang, Y.M. Zheng, Q.B. Mei, et al., FKBP12,6 and cADPR regulation of Ca~(2+) release in smooth muscle cells, Am. J. Physiol.Cell Physiol. 286 (2004) C538–C546.
13. Y.S. Prakash, M.S. Kannan, T.F. Walseth, G.C. Sieck, Role of cyclic ADP-ribose in the regulation of [Ca~(2+)]i in porcine tracheal smooth muscle, Am. J. Physiol. 274 (1998) C1653–C1660.
14. A.J. Lokuta, A. Darszon, C. Beltran, H.H. Valdivia, Detection and functional characterization of ryanodine receptors from sea urchin eggs, J. Physiol. 510 (1998) 155–164.
15. C.F. Perez, J.J. Marengo, R. Bull, C. Hidalgo, Cyclic ADP-ribose activates caffeine-sensitive calcium channels from sea urchin egg microsomes, Am. J. Physiol. 274 (1998) C430–C439.
16. L.G. Meszaros, J. Bak, A. Chu, Cyclic ADP-ribose as an endogenous regulator of the non-skeletal type ryanodine receptor Ca~(2+) channel,Nature 364 (1993) 76–79.
17. R. Sitsapesan, S.J. McGarry, A.J. Williams, Cyclic ADP-ribose, the ryanodine receptor and Ca~(2+) release, Trends Pharmacol. Sci. 16(1995) 386–391.
18. B.R. Fruen, J.R. Mickelson, N.H. Shomer, P.Velez, C.F. Louis, Cyclic ADP-ribose does not affect cardiac or skeletal muscle ryanodine receptors, FEBS Lett. 352 (1994) 123–126.
19. A.M. Evans, C.N.Wyatt, N.P. Kinnear, J.H. Clark, E.A. Blanco, Pyridine nucleotides and calcium signalling in arterial smooth muscle:from cell physiology to pharmacology, Pharmacol. Ther. 107 (2005)286–313.
20. J.M. Thomas, R. Masgrau, G.C. Churchill, A. Galione, Pharmacological characterization of the putative cADP-ribose receptor, Biochem.J. 359 (2001) 451– 457.
21. T.F. Walseth, R. Aarhus, J.A. Kerr, H.C. Lee, Identification of cyclic ADP-ribose- binding proteins by photoaffinity labeling, J. Biol. Chem.268 (1993) 26686–26691.
22. C. Franzini-Armstrong, F. Protasi, Ryanodine receptors of striated muscles: a complex channel capable of multiple interactions, Physiol.Rev. 77 (1997) 699-729.
23. M.G. Chelu, C.I. Danila, C.P. Gilman, S.L. Hamilton, Regulation of ryanodine receptors by FK506 binding proteins, Trends Cardiovasc.Med. 14 (2004) 227–234.
24. N. Noguchi, S. Takasawa, K. Nata, et al., Cyclic ADP-ribose binds to FK506-binding protein 12.6 to release Ca~(2+) from islet microsomes,J. Biol. Chem. 272 (1997) 3133–3136.
25. K.N. Bradley, S. Currie, D. MacMillan, T.C. Muir, J.G. McCarron,Cyclic ADP-ribose increases Ca~(2+) removal in smooth muscle, J. Cell Sci. 116 (2003) 4291–4306.
26. J.A. Copello, Y. Qi, L.H. Jeyakumar, E. Ogunbunmi, S. Fleischer,Lack of effect of cADP-ribose and NAADP on the activity of skeletal muscle and heart ryanodine receptors, Cell Calcium 30 (2001)269-284.
27. G. Bultynck, P. De Smet, D. Rossi, et al., Characterization and mapping of the 12 kDa FK506-binding protein (FKBP12)—binding site on different isoforms of the ryanodine receptor and of the inositol 1,4,5-trisphosphate receptor, Biochem. J. 354 (2001) 413–422.
28. W.X. Tang, Y.F. Chen, A.P. Zou, W.B. Campbell, P.L. Li, Role of FKBP12.6 incADPR-induced activation of reconstituted ryanodine receptors from arterial smooth muscle, Am. J. Physiol. Heart Circ.Physiol. 282 (2002) H1304–H1310.
29. G. Bultynck, D. Rossi, G. Callewaert, et al., The conserved sites for the FK506- binding proteins in ryanodine receptors and inositol 1,4,5-trisphosphate receptors are structurally and functionally different, J.Biol. Chem. 276 (2001) 47715–47724.
30. E.D. Moore, T. Voigt, Y.M. Kobayashi, et al., Organization of Ca~(2+) release units in excitable smooth muscle of the guinea-pig urinarybladder, Biophys. J. 87 (2004) 1836–1847.
31. H.J. Schatzmann, The calcium pump of the surface membrane and ofthe sarcoplasmic reticulum, Annu. Rev. Physiol. 51 (1989) 473–485.
32. Lukyanenko, V., Gyorke, I., Wiesner, T. F., & Gyorke, S. (2001).Potentiation of Ca(2+) release by cADP-ribose in the heart is mediated by enhanced SR Ca(2+) uptake into the sarcoplasmic reticulum. Circ Res 89, 614–622.
33. Rakovic, S., & Terrar, D. A. (2002). Terrar. Calcium signaling by cADPR in cardiac myocytes. In H. C. Lee (Ed.), Cyclic ADP-ribose and NAADP.Structures, Metabolism and Functions (pp. 331– 333). Dordrecht Kluwer Academic Publishing.
34. Itoh, M., Ishihara, K., Tomizawa, H., Tanaka, H., Kobune, Y., Ishikawa, J.,et al. (1994). Molecular cloning of murine BST-1 having homology with CD38 and Aplysia ADP-ribosyl cyclase. Biochem Biophys Res Commun 203, 1309– 1317.
35. Collier, M. L., Ji, G., Wang, Y., & Kotlikoff, M. I. (2000). Calcium-induced calcium release in smooth muscle: loose coupling between the action potential and calcium release. J Gen Physiol 115, 653–662.
36. Zhang, A. Y., Yi, F., Teggatz, E. G., Zou, A. P., & Li, P. L. (2004).Enhanced production and action of cyclic ADP-ribose during oxidative stress in small bovine coronary arterial smooth muscle. Microvasc Res 67, 159–167.
37. Katsuyama, H., Ito, S., Itoh, T., & Kuriyama, H. (1991). Effects of ryanodine on acetylcholine-induced Ca~(2+) mobilization in single smooth muscle cells of the porcine coronary artery. Pflugers Arch 419, 460-466.
38. Geiger, J., Zou, A. P., Campbell, W. B., & Li, P. L. (2000). Inhibition of cADP-ribose formation produces vasodilation in bovine coronary arteries. Hypertension 35, 397-402.
39. Kuemmerle, J. F., & Makhlouf, G. M. (1995). Agonist-stimulated cyclic ADP ribose. Endogenous modulator of Ca~(2+)-induced Ca~(2+) release in intestinal longitudinal muscle. J Biol Chem 270, 25488–25494.
40. Higashida, H., Yokoyama, S., Hashii, M., Taketo, M., Higashida, M.,Takayasu, T., et al. (1997). Muscarinic receptor-mediated dual regulation of ADP-ribosyl cyclase in NG108-15 neuronal cell membranes.J Biol Chem 272, 31272–31277.
41. Prakash, Y. S., Kannan, M. S., Walseth, T. F., & Sieck, G. C. (1998). Roleof cyclic ADP-ribose in the regulation of [Ca~(2+)]i in porcine tracheal smooth muscle. Am J Physiol 274, C1653-C1660.
42. Ge, Z. D., Zhang, D. X., Chen, Y. F., Yi, F. X., Zou, A. P., Campbell, W. B.,et al. (2003). Cyclic ADP-ribose contributes to contraction and Ca~(2+) release by M1 muscarinic receptor activation in coronary arterial smooth muscle. J Vasc Res 40, 28– 36.
43. Bailey, V. C., Sethi, J. K., Fortt, S. M., Galione, A., & Potter, B. V. (1997).7-Deaza cyclic adenosine 5V-diphosphate ribose: first example of a Ca~(2+)-mobilizing partial agonist related to cyclic adenosine 5V-diphosphate ribose. Chem Biol 4, 51-61.
44. Li, P. L., Zou, A. P., & Campbell, W. B. (1998b). Regulation of KCachannel activity by cyclic ADP-ribose and ADP-ribose in coronary arterial smooth muscle. Am J Physiol 275, H1002– H1010.
45. Bailey, V. C., Sethi, J. K., Fortt, S. M., Galione, A., & Potter, B. V. (1997).7-Deaza cyclic adenosine 5V-diphosphate ribose: first example of a Ca~(2+)-mobilizing partial agonist related to cyclic adenosine 5V-diphosphate ribose. Chem Biol 4, 51-61.
46. Campbell, W. B., Gebremedhin, D., Pratt, P. F., & Harder, D. R. (1996).Identification of epoxyeicosatrienoic acids as endothelium-derived hyperpolarizing factors. Circ Res 78, 415-423.
47. Li, P. L., Zhang, D. X., Ge, Z. D., & Campbell,W. B. (2002). Role of ADPribose in 11,12-EET-induced activation of K(Ca) channels in coronary arterial smooth muscle cells. Am J Physiol Heart Circ Physiol 282,H1229-H1236.
48. Wellman, G. C., Santana, L. F., Bonev, A. D., & Nelson, M. T. (2001). Role of phospholamban in the modulation of arterial Ca(2+) sparks and Ca(2+)-activated K(+) channels by cAMP. Am J Physiol Cell Physiol 28, C1029-C1037.
49. Boittin, F. X., Dipp, M., Kinnear, N. P., Galione, A., & Evans, A. M. (2003).Vasodilation by the calcium-mobilizing messenger cyclic ADPribose.J Biol Chem 278, 9602– 9608.
50. Kannan, M. S., Prakash, Y. S., Johnson, D. E., & Sieck, G. C. (1997b).Nitric oxide inhibits calcium release from sarcoplasmic reticulum of porcine tracheal smooth muscle cells. Am J Physiol 272, L1-L7.
51. White, T. A., Walseth, T. F., & Kannan, M. S. (2002). Nitric oxide inhibits ADP-ribosyl cyclase through a cGMP-independent pathway in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 283,L1065-L1071.
52. Wellman, G. C., Santana, L. F., Bonev, A. D., & Nelson, M. T. (2001). Role of phospholamban in the modulation of arterial Ca(2+) sparks and Ca(2+)-activated K(+) channels by cAMP. Am J Physiol Cell Physiol 28, C1029–C1037.
53. Fuchs, A. R. (1995). Plasma, membrane receptors regulating myometrial contractility and their hormonal modulation. Semin Perinatol 19,15-30.
54. Sanborn, B. M., Qian, A., Ku, C. Y., Wen, Y., Anwer, K., Monga, M., et al.(1995). Mechanisms regulating oxytocin receptor coupling to phospholipase C in rat and human myometrium. Adv Exp Med Biol 39, 469-479.
55. Berridge, M. J. (1993). Inositol trisphosphate and calcium signalling.Nature 361, 315–325.
56. Lynn, S., Morgan, J. M., Lamb, H. K., Meissner, G., & Gillespie, J. I.(1995). Isolation and partial cloning of ryanodine-sensitive Ca~(2+) release channel protein isoforms from human myometrial smooth muscle.FEBS Lett 18, 6-12.
57. Chini, E. N., de Toledo, F. G., Thompson, M. A., & Dousa, T. P. (1997).Effect of estrogen upon cyclic ADP ribose metabolism: beta-estradiol stimulates ADP ribosyl cyclase in rat uterus. Proc Natl Acad Sci USA 94, 5872-5876.
58. Wu, X., Pang, S. T., Sahlin, L., Blanck, A., Norstedt, G., & Flores-Morales,A. (2003). Gene expression profiling of the effects of castration and estrogen treatment in the rat uterus. Biol Reprod 69, 1308-1317.
59. Blatter, L. A., & Wier, W. G. (1994). Nitric oxide decreases [Ca~(2+)]_i in vascular smooth muscle by inhibition of the calcium current. Cell Calcium 15, 122-131.
60. Dogan, S., Deshpande, D. A., Kannan, M. S., & Walseth, T. F. (2004).Changes in CD38 expression and ADP-ribosyl cyclase activity in rat myometrium duringpregnancy: influence of sex steroid hormones. Biol Reprod 71, 97-103.
61. Chini, E. N., de Toledo, F. G., Thompson, M. A., & Dousa, T. P. (1997).Effect of estrogen upon cyclic ADP ribose metabolism: beta-estradiol stimulates ADP ribosyl cyclase in rat uterus. Proc Natl Acad Sci USA 94, 5872– 5876.
62. Chini, E. N., Chini, C. C., Barata da Silva, S., & Zielinska, W. (2002). The cyclic-ADP-ribose signaling pathway in human myometrium. Arch Biochem Biophys 407, 152–159.
63. Dogan, S., White, T. A., Deshpande, D. A., Murtaugh, M. P., Walseth, T. F., & Kannan, M. S. (2002). Estrogen increases CD38 gene expression and leads to differential regulation of adenosine diphosphate (ADP)-ribosyl cyclase and cyclic ADP-ribose hydrolase activities in rat myometrium.Biol Reprod 66, 596-602.
64. Hardingham, G. E., Chawla, S., Johnson, C. M., & Bading, H. (1997).Distinct functions of nuclear and cytoplasmic calcium in the control of gene expression. Nature 385, 260-265.
65. Romanini, C. (1994). In T. Chard, & J. G. Grudzinskas (Eds.), The Uterus(pp. 337– 355). Cambridge7 Cambridge Univ. Press.
66. Tliba, O., Panettieri Jr., R. A., Tliba, S., Walseth, T. F., & Amrani, Y.(2004). Tumor necrosis factor-{alpha} differentially regulates the expression of proinflammatory genes in human airway smooth muscle cells by activation of interferon-{beta}- dependent CD38 pathway. Mol Pharmacol 66, 322– 329.
67. Deshpande, D. A., Dogan, S., Walseth, T. F., Miller, S. M., Amrani, Y.,Panettieri, R. A., et al. (2004). Modulation of calcium signaling by interleukin-13 in human airway smooth muscle: role of CD38/cyclic adenosine diphosphate ribose pathway. Am J Respir Cell Mol Biol 31,36-42.
68. Chidambaram, N., Wong, E. T., & Chang, C. F. (1998).Differentialoligomerization of membrane-bound CD38/ADP-ribosyl cyclase in porcine heart microsomes. Biochem Mol Biol Int 44, 1225-1233.
2. Li L, Jiang C, Song B, Yan J, Pan J.Altered expression of calcium-activated K and Cl channels in detrusor overactivity of rats with partial bladder outlet obstruction.BJU Int. 2008 Jun;101(12):1588-94..
3.卢根生,金锡御,宋波.逼尿肌不稳定超微结构改变的实验研究.解放军医学杂志,2002,27(3):219-220.
4. Jiang HH, Song B, Lu GS, etc. Loss of ryanodine receptor calcium-release channel expression associated with overactive urinary bladder smooth muscle contractions in a detrusor instability model. BJU Int, 2005,96 (3):428-33.
5. Li L, Qiu G, Hao P, Song B. Effect of partial bladder outlet obstruction on detrusor compliance, excitability and contractility in rats. Scand J Urol Nephrol, 2006, 40(4):293-9.
6. Meng E, Young JS, Brading AF.Spontaneous activity of mouse detrusor smooth muscle and the effects of the urothelium.Neurourol Urodyn. 2008;27(1):79-87.
7. de Groat WC. A neurologic basis for the overactive bladder.Urology,1997 Dec;50(6A Suppl):36-52; discussion 53-6.
8. Brading A F. A myogenic basis for the overactive bladder. Urology,1997,50(6A Supp l):57-67,68-73.
9. Sanders KM, Koh SD, Ward SM. Interstitial cells of cajal as pacemakers in the gastrointestinal tract. Annu Rev Physiol 2006; 68: 307-343.
10. Megan F. Klemm, Betty Exintaris and R. J. Lang. Identification of the cells underlying pacemaker activity in the guinea-pig upper urinary tract. The Journal of Physiology, 1999, 519(3): 867-884.
11. McCloskey, K. D. and A. M. Gurney.Kit positive cells in the guinea pig bladder.J Urol,2002,168(2):832-6.
12. Shafik A,El-Sibai O, Shafik A A, et al.Identification of interstitial cells of Cajal in human urinary bladder: concept of vesical pacemaker. Urology, 2004, 64 (4):809-813.
13. McCloskey KD. Characterization of outward currents in interstitial cells from theguinea p ig bladder.J Urol,2005,173(1):296-301.
14. Kubota Y, Biers SM, Kohri K, et al. Effects of imatinib mesylate(Glivec) as a c-kit tyrosine kinase inhibitor in the guinea pig urinary bladder.Neurourol Urodyn,2006, 25(3):205-210.
15. Biers SM, Reynard J M, Doore T, et al. The functional effects of a c-kit tyrosine inhibitor on guinea pig and human detrusor .BJU Int,2006,97(3):612-616.
16. Montgomery BS, Fry CH. The action potential and net membrane currents in isolated human detrusor smooth muscle cell.J Urol,1992,147,176-184.
17. Sui GP, Wu C, Fry CH. The electrophysiological properties of cultured and freshly isolated detrusor smooth muscle cells. J Urol. 2001,165(2):627-32.
18. Hashitani H, Fukuta H, Takano H, Klemm MF, Suzuki H.Origin and propagation of spontaneous excitation in smooth muscle of the guinea-pig urinary bladder.J Physiol. 2001 Jan 15;530(Pt 2):273-86.
19. Berridge MJ. Inositol trisphosphate and calcium signalling. Nature.1993;361:315–325.
20. Nelson, M.T., H. Cheng, M. Rubart, L.F. Santana, A.D. Bonev, H.J. Knot, and W.J. Lederer. Relaxation of arterial smooth muscle by calcium sparks. Science. 1995;270:633–637.
21. Lam E, Martin MM, Timerman AP, Sabers C, Fleischer S, Lukas T, Abraham RT, O'Keefe SJ, O'Neill EA, Wiederrecht GJ. A Novel FK506 Binding Protein Can Mediate the Immunosuppressive Effects of FK506 and Is Associated with the Cardiac Ryanodine Receptor.J Biol Chem. 1995 Nov 3;270(44):26511-22.
22. Xin HB, Rogers K, Qi Y, Kanematsu T, Fleischer S. Three amino acid residues determine selective binding of FK506-binding protein 12.6 to the cardiac ryanodine receptor. J. Biol. Chem. 1999;24- 274:15315-15319.
23. Ji G, Feldman ME, Greene KS, Sorrentino V, Xin HB, Kotlikoff MI. RYR2 Proteins Contribute to the Formation of Ca~(2+) Sparks in Smooth Muscle. J Gen Physiol. 2004 April; 123(4): 377–386.
24. Yano M, Kobayashi S, Kohno M, Doi M, Tokuhisa T, Okuda S, Suetsugu M, Hisaoka T, Obayashi M, Ohkusa T, Kohno M, Matsuzaki M. FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure.Circulation. 2003 Jan 28;107(3):477-84.
25. Huang F, Shan J, Reiken S, Wehrens XH, Marks AR.Analysis of calstabin2 (FKBP12.6) -ryanodine receptor interactions: rescue of heart failure by calstabin2 in mice. Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3456-61.
26. Xin HB, Rogers K, Qi Y, Kanematsu T, Fleischer S. Three amino acid residues determine selective binding of FK506-binding protein 12.6 to the cardiac ryanodine receptor. J. Biol. Chem. 1999;24- 274:15315-15319.
27. Xin HB, Senbonmatsu T, Cheng DS, Wang YX, Copello JA, Ji GJ, Collier ML, Deng KY, Jeyakumar LH, Magnuson MA, Inagami T, Kotlikoff MI, Fleischer S. Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy. Nature. 2002;416:334-338.
28. Prestle J, Janssen PM, Janssen AP, Zeitz O, Lehnart SE, Bruce L, Smith GL, Hasenfuss G. Overexpression of FK506-binding protein FKBP12.6 in cardiomyocytes reduces ryanodine receptor-mediated Ca(2+) leak from the sarcoplasmic reticulum and increases contractility.Circ Res. 2001 Feb 2;88(2):188-94.
29. Gómez AM, Schuster I, Fauconnier J, Prestle J, Hasenfuss G, Richard S. FKBP12.6 overexpression decreases Ca~(2+) spark amplitude but enhances [Ca~(2+)]i transient in rat cardiac myocytes. Am J Physiol Heart Circ Physiol. 2004 Nov;287(5):H1987-93.
30. Timerman AP, Onoue H, Xin HB, Barg S, Copello J, Wiederrecht G, Fleischer S. Selective binding of FKBP12.6 by the cardiac ryanodine receptor. J. Biol. Chem. 1996,271:20385–20391.
31. Noguchi N, Takasawa S, Nata K, Tohgo A, Kato I, Ikehata F, Yonekura H, Okamoto H.Cyclic ADP-ribose binds to FK506-binding protein 12.6 to release Ca~(2+) from islet microsomes. J Biol Chem. 1997;272:3133–3136.
32. Tang WX, Chen YF, Zou AP, Campbell WB, Li PL. Role of FKBP12.6 in cADPR-induced activation of reconstituted ryanodine receptors from arterial smooth muscle. Am J Physiol Heart Circ Physiol. 2002;282:H1304–H1310.
33. Wang YX, Zheng YM, Mei QB, Wang QS, Collier ML, Fleischer S, Xin HB, Kotlikoff MI.FKBP12.6 and cADPR regulation of Ca~(2+) release in smooth muscle cells. Am J Physiol Cell Physiol.2004;286:C538 -C546.
34. Fruen BR, Mickelson JR, Shomer NH, Velez P, Louis CF. Cyclic ADP-ribose does not affect cardiac or skeletal muscle ryanodine receptors. FEBS Lett. 1994 Sep 26;352(2): 123-6.
35. Guo X, Laflamme MA, Becker PL. Cyclic ADP-ribose does not regulate sarcoplasmicreticulum Ca~(2+) release in intact cardiac myocytes. Circ Res. 1996 Jul;79(1):147-51.
36. Copello JA, Qi Y, Jeyakumar LH, Ogunbunmi E, Fleischer S. Lack of effect of cADP-ribose and NAADP on the activity of skeletal muscle and heart ryanodine receptors. Cell Calcium. 2001 Oct;30(4):269-84.
37. Cheung DW.Modulation of spontaneous transient Ca~(2+)-activated K+ channel currents by cADP-ribose in vascular smooth muscle cells..Eur J Pharmacol. 2003 Jan 1;458(1-2):57-9.
38. McCarron JG, Chalmers S, Bradley KN, MacMillan D, Muir TC.Ca~(2+) microdomains in smooth muscle.Cell Calcium. 2006 Nov-Dec;40(5-6):461-93.
39. Lukyanenko V, Gy?rke I, Wiesner TF, Gy?rke S. Potentiation of Ca(2+) release by cADP-ribose in the heart is mediated by enhanced SR Ca(2+) uptake into the sarcoplasmic reticulum.Circ Res. 2001 Sep 28;89(7):614-22.
40. G. P. Sergeant, K. D. Thornbury, N. G. McHale, M. A. Hollywood. Interstitial cells of Cajal in the urethra. J. Cell. Mol. Med. Vol 10, No 2, 2006 pp. 280-291
41. Christensen J. A commentary on the morphological identification of interstitial cells of Cajal in the gut. J Auton Nerv Syst,1992;37:75-88
42. Shuttleworth CW, Xue C, Ward SM, de Vente J, Sanders KM. Immunohistochemical localization of 3', 5'-cyclicguanosine monophosphate in the canine proximal colon: responses to nitric oxide and electrical stimulation of enteric inhibitory neurons. Neuroscience, 1993;56:513-522
43. Young HM, McConalogue K, Furness JB, de Vente J. Nitric oxide targets in the guinea-pig intestine identified by induction of cyclic GMP immunoreactivity. Neuroscience, 1993;55:583-596
44. Xue C, Pollock J, Schmidt HHHW, Ward SM, Sanders KM. Expression of nitric oxide synthase by interstitial cells of the canine proximal colon. J Auton Nerv Syst, 1994;49:1-14
45. Komuro T, Zhou DS. Anti-c-kit protein immunoreactive cells corresponding to the interstitial cells of Cajal in the guinea-pig small intestine. J Auton Nerv Syst, 1996;61:169-174
45. Burns AJ, Herbert TM, Ward SM, Sanders KM. Interstitial cells of Cajal in the guinea-pig gastrointestinal tract as revealed by c-Kit immunohistochemistry. CellTissue Res, 1997;290:11-20
46. Wester T, Eriksson L, Olsson Y, Olsen L. Interstitial cells of Cajal in the human fetal small bowel as shown by c-kit immunohistochemistry. Gut, 1999;44:65-71
47. Kenny SE, Connell G, Woodward MN, Lloyd DA, Gosden CM, Edgar DH, Vaillant C. Ontogeny of interstitial cells of Cajal in the human intestine. J Pediatr Surg, 1999;34:1241-1247
48. Nakagawa T,Misawa H,Nakajima Y,et al.Absence of peristalsis in the ileum of W/W(V) mutant mice that are selectively deficient in myenteric interstitial cells of Cajia. J. Smooth Muscle Res.2005;41:141-151.
49. Yanagida H, Yanase H, Sanders KM, et al. Intestinal surgical resection disrupts electrical rhythmicity, neural responses, and interstitial cell networks. Gastroenterology. 2004;127(6):1748-1759.
50. Hashitani H, Brading AF, Suzuki H. Correlation between spontaneous electrical, calcium and mechanical activity in detrusor smooth muscle of the guinea-pig bladder. Br J Pharmacol,2004,141(1):183-93.
51. Kuo KH, Dai J, Seow CY, Lee CH, van Breemen C.Relationship between asynchronous Ca~(2+) waves and force development in intact smooth muscle bundles of the porcine trachea.Am J Physiol Lung Cell Mol Physiol. 2003 Dec;285(6):L1345-53.
52. Yanai Y, Hashitani H, Kubota Y, Sasaki S, Kohri K, Suzuki H.The role of Ni(2+)-sensitive T-type Ca(2+) channels in the regulation of spontaneous excitation in detrusor smooth muscles of the guinea-pig bladder.BJU Int. 2006 Jan;97(1):182-9.
53. Burdyga T, Shmygol A, Eisner DA, Wray S.A new technique for simultaneous and in situ measurements of Ca~(2+) signals in arteriolar smooth muscle and endothelial cells. Cell Calcium. 2003 Jul;34(1):27-33.
54.李龙坤,宋波.膀胱ICCs细胞与逼尿肌兴奋性关系研究现状.第三军医大学学报,2008,30(7):555-557.
55. McCloskey KD.Calcium currents in interstitial cells from the guinea-pig bladder.BJU Int. 2006 Jun;97(6):1338-43.
56. Heppner, T. J., A. D. Bonev, et al. (2005). "Elementary purinergic Ca~(2+) transients evoked by nerve stimulation in rat urinary bladder smooth muscle." J Physiol 564(Pt 1): 201-12.
57. Hashitani, H. , Bramich, N. J. & Hirst, G. D. S. (2000). Mechanisms of excitatory neuromuscular transmission in the guinea pig urinary bladder. Journal of Physiology 524, 565-579.
58. Li L, Jiang C, Hao P, Li W, Song C, Song B. Changes of gap junctional cell-cell communication in overactive detrusor in rats. Am J Physiol Cell Physiol. 2007,293(5):C1627-35.
59. Kim JC, Yoo JS, Park EY, Hong SH, Seo SI, Hwang TK.Muscarinic and purinergic receptor expression in the urothelium of rats with detrusor overactivity induced by bladder outlet obstruction.BJU Int. 2008 Feb;101(3):371-5.
60. Watanabe T, Omata S, Lee JZ, Constantinou CE.Comparative analysis of bladder wall compliance based on cystometry and biosensor measurements during the micturition cycle of the rat.Neurourol Urodyn. 1997;16(6):567-81.
61. Meng E, Young JS, Brading AF.Spontaneous activity of mouse detrusor smooth muscle and the effects of the urothelium.Neurourol Urodyn. 2008;27(1):79-87.
62. McCloskey KD, Anderson UA, Davidson RA, Bayguinov YR, Sanders KM, Ward SM.Comparison of mechanical and electrical activity and interstitial cells of Cajal in urinary bladders from wild-type and W/Wv mice.Br J Pharmacol. 2009 Jan; 156(2):273-83.
63. Brading AF, McCloskey KD.Mechanisms of Disease: specialized interstitial cells of the urinary tract--an assessment of current knowledge.Nat Clin Pract Urol. 2005 Nov;2(11):546-54.
64. Davidson RA, McCloskey KD.Morphology and localization of interstitial cells in the guinea pig bladder: structural relationships with smooth muscle and neurons.J Urol. 2005 Apr;173(4):1385-90.
65. Hashitani H, Hayase M, Suzuki H.Effects of imatinib mesylate on spontaneous electrical and mechanical activity in smooth muscle of the guinea-pig stomach.Br J Pharmacol. 2008 May;154(2):451-9. Epub 2008 Apr 14.
66. Lang, R. J. and M. F. Klemm. Interstitial cell of Cajal-like cells in the upper urinary tract[J]. J Cell Mol Med,2005,9(3): 543-56.
67.封建立,方强,丁砺蠡,宋波等.ICCs细胞在正常大鼠膀胱中的分布及对逼尿肌收缩的影响[J].第三军医大学学报,2008,30(7):558-560.
68. Johnston, L., C. Carson, et al. Cholinergic-induced Ca~(2+) signaling in interstitial cells of Cajal from the guinea pig bladder.Am J Physiol Renal Physiol, 2008, 294(3):F645-55.
69. Hashitani, H. and H. Suzuki.Properties of spontaneous Ca~(2+) transients recorded from interstitial cells of Cajal-like cells of the rabbit urethra in situ.J Physiol,2007,583(Pt 2):505-19.
70. Guangju Ji,Morris Feldman,Robert Doran,Warren Zipfel,and Michael I. Kotlikoff.Ca~(2+)-Induced Ca~(2+) Release through Localized Ca~(2+) Uncaging in Smooth Muscle. J Gen Physiol. 2006 March; 127(3):225-235.
71. Fritz N, Morel JL, Jeyakumar LH, Fleischer S, Allen PD, Mironneau J, Macrez N. RyR1-specific requirement for depolarization-induced Ca~(2+) sparks in urinary bladder smooth muscle.J Cell Sci. 2007 Nov 1;120(Pt 21):3784-91.
72. Lang RJ, Davidson ME & Exintaris B (2002). Pyeloureteralmotility and ureteral peristalsis. essential role of sensorynerves and endogenous prostaglandins. Exp Physiol 87,129–146.
73. Van Helden DF (1993). Pacemaker potentials in lymphaticsmooth muscle of the guinea-pig mesentery. J Physiol 471,465–479.
74. Bortoff A (1976). Myogenic control of intestinal motility.Physiol Rev 56, 418–434.
75. Axelsson J,Wahlstrom B, Johansson B & Jonsson O (1967).Influence of the ionic environment on spontaneous electricaland mechanical activity of the rat portal vein. Circ Res 21,609–618.
76. Bengtsson B, Chow EM & Marshall JM (1984). Activity ofcircular muscle of rat uterus at different times in pregnancy.Am J Physiol 246, C216–223.
77. Brading AF, Teramoto N, Dass N & McCoy R (2001).Morphological and physiological characteristics of urethralcircular and longitudinal smooth muscle. Scand J Urol Nephrol Suppl 207, 12-18.
78. Hayase M, Hashitani H, Kohri K, Suzuki H.Role of K(+) Channels in Regulating Spontaneous Activity in Detrusor Smooth Muscle In Situ in the Mouse Bladder.J Urol. 2009 Mar 18. [Epub ahead of print]
79. Hashitani H, Brading AF.Electrical properties of detrusor smooth muscles from the pig and human urinary bladder.Br J Pharmacol. 2003 Sep;140(1):146-58.
80. Domae K, Hashitani H, Suzuki H.Regional differences in the frequency of slow wavesin smooth muscle of the guinea-pig stomach.J Smooth Muscle Res. 2008 Dec;44(6):231-48.
81. van Helden DF, Imtiaz MS, Nurgaliyeva K, von der Weid P, Dosen PJ.Role of calcium stores and membrane voltage in the generation of slow wave action potentials in guinea-pig gastric pylorus.J Physiol. 2000 Apr 1;524 Pt 1:245-65.
82. Sergeant GP, Craven M, Hollywood MA, McHale NG, Thornbury KD.Spontaneous Ca~(2+) waves in rabbit corpus cavernosum: modulation by nitric oxide and cGMP.J Sex Med. 2009 Apr;6(4):958-66. Epub 2008 Dec 9.
83. Lang RJ, Tonta MA, Zoltkowski BZ, et al. Pyeloureteric peristalsis: role of atypical smooth muscle cells and interstitial cells of Cajal-like cells as pacemakers.J Physiol 2006;576(Pt 3):695-705.
84. Johnston L, Sergeant GP, Hollywood MA, et al. Calcium oscillations in interstitial cells of the rabbit urethra.J Physiol 2005;565(Pt 2):449-461
85. Sergeant GP, Hollywood MA, McCloskey KD, McHale NG, Thornbury KD. Role of IP(3) in modulation of spontaneous activity in pacemaker cells of rabbit urethra. Am J Physiol Cell Physiol. 2001; 280: C1349-56.
86. Sergeant GP, Bradley E, Thornbury KD, McHale NG, Hollywood MA.Role of mitochondria in modulation of spontaneous Ca~(2+) waves in freshly dispersed interstitial cells of Cajal from the rabbit urethra.J Physiol. 2008 Oct 1;586(Pt 19):4631-42.
87. Han C, Tavi P, Weckstr?m M.Role of the Na(+)-Ca(2+) exchanger as an alternative trigger of CICR in mammalian cardiac myocytes.Biophys J. 2002 Mar;82(3):1483-96.
88. Kitchens SA, Burch J, Creazzo TL.T-type Ca~(2+) current contribution to Ca~(2+)-induced Ca~(2+) release in developing myocardium.J Mol Cell Cardiol. 2003 May;35(5):515-23.
89. Walker RL, Koh SD, Sergeant GP, Sanders KM, Horowitz B. TRPC4 currents have properties similar to the pacemaker current in interstitial cells of Cajal. Am J Physiol Cell Physiol. 2002; 283: C1637-45.
90. Fritz N, Morel JL, Jeyakumar LH, Fleischer S, Allen PD, Mironneau J, Macrez N. RyR1-specific requirement for depolarization-induced Ca~(2+) sparks in urinary bladder smooth muscle.J Cell Sci. 2007 Nov 1;120(Pt 21):3784-91.
91. Mészáros LG, Bak J, Chu A. Cyclic ADP-ribose as an endogenous regulator of the non-skeletal type ryanodine receptor Ca~(2+) channel. Nature. 1993;364:76–79.
92. Clementi E, Riccio M, Sciorati C, Nistico G, and Meldolesi J. The type 2 ryanodine receptor of neurosecretory PC12 cells is activated by cyclic ADP-ribose. Role of the nitric oxide/cGMP pathway. J Biol Chem. 1996;271:17739-45.
93. Walsh JV Jr, Singer JJ.Ca++ activated K+ channels in vertebrate smooth muscle cells. Cell Calcium. 1983;4:321-330.
94. Trieschmann U, Isenberg G. Ca~(2+) activated K+ channels contribute to the resting potential of vascular myocytes. Ca~(2+) sensitivity is increased by intracellular Mg2+ ions. Pflugers Arch. 1989;414:S183–S184.
95. Wang, Y.X., B.K. Fleischmann, and M.I. Kotlikoff. Modulation of maxi-K+ channels by voltage-dependent Ca~(2+) channels and methacholine in single airway myocytes. Am. J. Physiol. 1997;272:C1151-C1159.
96. Su Z, Sugishita K, Li F, Ritter M, Barry WH. Effects of FK506 on [Ca~(2+)]i differ in mouse and rabbit ventricular myocytes. J Pharmacol Exp Ther. 2003 Jan;304 (1):334-41.
97. Iino S, Cui Y, Galione A, Terrar DA. Actions of cADP-ribose and its antagonists on contraction in guinea pig isolated ventricular myocytes. Influence of temperature.Circ Res. 1997 Nov;81(5):879-84.
98. Lehnart SE, Terrenoire C, Reiken S, Wehrens XH, Song LS, Tillman EJ, Mancarella S, Coromilas J, Lederer WJ, Kass RS, Marks AR. Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias.Proc Natl Acad Sci U S A. 2006 May 16;103 (20):7906-10.
99. Galione A, Lee HC, Busa WB. Ca~(2+)-induced Ca~(2+) release in sea urchin egg homogenates: modulation by cyclic ADP-ribose.Science. 1991; 253:1143– 1146.
100. Li PL, Tang WX, Valdivia HH, Zou AP, Campbell WB.cADP-ribose activates reconstituted ryanodine receptors fromcoronary arterial smooth muscle. Am J Physiol Heart Circ Physiol. 2001;280:H208–H215.
101. Perez, GJ, Bonev, AD, Patlak, JB and Nelson, MT. Functional coupling of ryanodine receptors to KCa channels in smooth muscle cells from rat cerebral arteries. J. Gen. Physiol.,1999,113:229- 238.
102. Xiao RP, Valdivia HH, Bogdanov K, Valdivia C, Lakatta EG, and Cheng H. The immunophilin FK506-binding protein modulates Ca~(2+) release channel closure in ratheart. J Physiol.1997;500: 343-354.
103. McCall E, Li L, Satoh H, Shannon TR, Blatter LA, Bers DM. Effects of FK-506 on contraction and Ca~(2+) transients in rat cardiac myocytes.Circ Res. 1996 Dec;79(6):1110-21.
104. Loughrey CM, Seidler T, Miller SL, Prestle J, MacEachern KE, Reynolds DF, Hasenfuss G, Smith GL. Over-expression of FK506-binding protein FKBP12.6 alters excitation-contraction coupling in adult rabbit cardiomyocytes.J Physiol. 2004 May 1;556(Pt 3):919-34.
105. Morita K, Kitayama T, Kitayama S and Dohi T.Cyclic ADP-ribose requires FK506-binding protein to regulate intracellular Ca~(2+) dynamics and catecholamine release in acetylcholine-stimulated bovine adrenal chromaffin cells.J Pharmacol Sci. 2006 May; 101 (1):40-51.
106. Prakash YS, Kannan M, Walseth TF and Sieck GC. cADPR ribose and [Ca~(2+)]i regulation in rat cardiac myocytes. Am J Physiol Heart Circ Physiol. 2000; 279:1482-1489.
107. Brillantes AB, Ondrias K, Scott A, Kobrinsky E, OndriasováE, Moschella MC, J ayaraman T, Landers M, Ehrlich BE, Marks AR. Stabilization of calcium release channel (ryanodine receptor) function by FK506-binding protein.Cell. 1994 May 20;77(4):513-23.
108. Cui Y, Galione A, Terrar DA.Effects of photoreleased cADP-ribose on calcium transients and calcium sparks in myocytes isolated from guinea-pig and rat ventricle.Biochem J. 1999 Sep 1;342 ( Pt 2):269-73.
109. Iino S, Cui Y, Galione A, Terrar DA. Actions of cADP-ribose and its antagonists on contraction in guinea pig isolated ventricular myocytes. Influence of temperature.Circ Res. 1997 Nov;81(5):879-84.
110. Rakovic S, Galione A, Ashamu GA,et al.A specific cyclic ADP-ribose antagonist inhibits cardiac excitation-contraction coupling.Curr Biol. 1996 Aug 1;6(8):989-96.
111. ZhuGe R, Fogarty KE, Tuft RA, Lifshitz LM, Sayar K, Walsh JV Jr.Dynamics of signaling between Ca(2+) sparks and Ca(2+)- activated K(+) channels studied with a novel image-based method for direct intracellular measurement of ryanodine receptor Ca(2+) current.J Gen Physiol. 2000 Dec;116(6):845-64.
112. Y.X. Wang, Y.M. Zheng, Q.B. Mei, et al., FKBP12,6 and cADPR regulation of Ca~(2+) release in smooth muscle cells, Am. J. Physiol.Cell Physiol. 286 (2004) C538–C546.
113. Y.S. Prakash, M.S. Kannan, T.F. Walseth, G.C. Sieck, Role of cyclic ADP-ribose in the regulation of [Ca~(2+)]i in porcine tracheal smooth muscle, Am. J. Physiol. 274 (1998) C1653–C1660.
114. A.J. Lokuta, A. Darszon, C. Beltran, H.H. Valdivia, Detection and functional characterization of ryanodine receptors from sea urchin eggs, J. Physiol. 510 (1998) 155–164.
115. C.F. Perez, J.J. Marengo, R. Bull, C. Hidalgo, Cyclic ADP-ribose activates caffeine-sensitive calcium channels from sea urchin egg microsomes, Am. J. Physiol. 274 (1998) C430–C439.
116. L.G. Meszaros, J. Bak, A. Chu, Cyclic ADP-ribose as an endogenous regulator of the non-skeletal type ryanodine receptor Ca~(2+) channel,Nature 364 (1993) 76–79.
117. R. Sitsapesan, S.J. McGarry, A.J. Williams, Cyclic ADP-ribose, the ryanodine receptor and Ca~(2+) release, Trends Pharmacol. Sci. 16(1995) 386–391.
118. B.R. Fruen, J.R. Mickelson, N.H. Shomer, P.Velez, C.F. Louis, Cyclic ADP-ribose does not affect cardiac or skeletal muscle ryanodine receptors, FEBS Lett. 352 (1994) 123–126.
119. A.M. Evans, C.N.Wyatt, N.P. Kinnear, J.H. Clark, E.A. Blanco, Pyridine nucleotides and calcium signalling in arterial smooth muscle:from cell physiology to pharmacology, Pharmacol. Ther. 107 (2005)286–313.
120. J.M. Thomas, R. Masgrau, G.C. Churchill, A. Galione, Pharmacological characterization of the putative cADP-ribose receptor, Biochem.J. 359 (2001) 451–457.
121. T.F. Walseth, R. Aarhus, J.A. Kerr, H.C. Lee, Identification of cyclic ADP-ribose-binding proteins by photoaffinity labeling, J. Biol. Chem.268 (1993) 26686–26691.
122. C. Franzini-Armstrong, F. Protasi, Ryanodine receptors of striated muscles: a complex channel capable of multiple interactions, Physiol.Rev. 77 (1997) 699-729.
123. M.G. Chelu, C.I. Danila, C.P. Gilman, S.L. Hamilton, Regulation of ryanodine receptors by FK506 binding proteins, Trends Cardiovasc.Med. 14 (2004) 227–234.
124. N. Noguchi, S. Takasawa, K. Nata, et al., Cyclic ADP-ribose binds to FK506-bindingprotein 12.6 to release Ca~(2+) from islet microsomes,J. Biol. Chem. 272 (1997) 3133–3136.
125. K.N. Bradley, S. Currie, D. MacMillan, T.C. Muir, J.G. McCarron,Cyclic ADP-ribose increases Ca~(2+) removal in smooth muscle, J. Cell Sci. 116 (2003) 4291–4306.
126. J.A. Copello, Y. Qi, L.H. Jeyakumar, E. Ogunbunmi, S. Fleischer,Lack of effect of cADP-ribose and NAADP on the activity of skeletal muscle and heart ryanodine receptors, Cell Calcium 30 (2001)269-284.
127. G. Bultynck, P. De Smet, D. Rossi, et al., Characterization and mapping of the 12 kDa FK506-binding protein (FKBP12)—binding site on different isoforms of the ryanodine receptor and of the inositol 1,4,5-trisphosphate receptor, Biochem. J. 354 (2001) 413–422.
128. W.X. Tang, Y.F. Chen, A.P. Zou, W.B. Campbell, P.L. Li, Role of FKBP12.6 in cADPR-induced activation of reconstituted ryanodine receptors from arterial smooth muscle, Am. J. Physiol. Heart Circ.Physiol. 282 (2002) H1304–H1310.
129. G. Bultynck, D. Rossi, G. Callewaert, et al., The conserved sites for the FK506-binding proteins in ryanodine receptors and inositol 1,4,5-trisphosphate receptors are structurally and functionally different, J.Biol. Chem. 276 (2001) 47715–47724.
130. E.D. Moore, T. Voigt, Y.M. Kobayashi, et al., Organization of Ca~(2+)release units in excitable smooth muscle of the guinea-pig urinarybladder, Biophys. J. 87 (2004) 1836–1847.
131. H.J. Schatzmann, The calcium pump of the surface membrane and ofthe sarcoplasmic reticulum, Annu. Rev. Physiol. 51 (1989) 473–485.
132. Liu HN, Ohya S, Furuzono S, Wang J, Imaizumi Y, Nakayama S. Co-contribution of IP3R and Ca~(2+) influx pathways to pacemaker Ca~(2+) activity in stomach ICC.J Biol Rhythms. 2005 Feb;20(1):15-26.
1. Cajal.S.R. Sur les ganglions et plexus nerveux de I'intestin. Compt Rend Soc Biol, 1893, 45:217-233.
2. Rogers DC, Burnstock G. The intersitial cell and its place in the concept of the autonomic ground plexus. J Comp Neurol. 1966,126, 255-284
3. Imaizumi M, Hama K. An electromicroscopic study on the interstitial cells of the gizzard in the love bird (Uronloncha domestica). Z Zellforsch Mikrosk Anat.1969, 97, 351-357.
4. Thuneberg L. Interstitial cells of Cajal: intestinal pacemaker cells? Adv Anat Embryol Cell Biol, 1982, 71:1-130.
5. Faussone-Pellegrini MS, Thuneberg L. Guide to the identification of interstitial cells of Cajal. Microsc Res Tech, 1999, 47(4):248-266.
6. Hanani M, Freund HR. Interstitial cells of Cajal--their role in pacing and signal transmission in the digestive system. Acta Physiol Scand, 2000, 170(3): 177-190.
7. Komuro T. Comparative morphology of interstitial cells of Cajal: ultrastructural characterization. Microsc Res Tech, 1999;47:267-285
8. Faussone-Pellegrini MS, Thuneberg L. Guide to the identification of interstitial cells of Cajal. Microsc Res Tech, 1999;47:248-266
9. Komuro T, Seki K, Horiguchi K. Ultrastructural characterization of the interstitial cells of Cajal. Arch Histol Cytol, 1999;62:295-316
10. Komuro T, Seki K, Horiguchi K. Ultrastructural characterization of the interstitial cells of Cajal. Arch Histol Cytol 1999; 62: 295-316
11. Kobayashi S. The structure of the autonomic and apparatus in the guinea-pig small intestine and the problem of the interstitial cells of Cajal. Acta Med Biol , 1990;38:103-127
12. Christensen J. A commentary on the morphological identification of interstitial cells of Cajal in the gut. J Auton Nerv Syst,1992;37:75-88
13. Zhou DS, Komuro T. Ultrastructure of the zinc iodide-osmic acid staining cells in guinea pig small intestine. J Anat,1995;187:481-485
14.童卫东,张胜本,张连阳,蔡文琴,杜文华,牟江洪.大鼠结肠肌间神经丛Cajal间质细胞的形态.解剖学杂志,1999;22:316-318
15. Ward SM, Burke EP, and Sanders KM.Use of rhodamine-123 to label and lesion interstitial cells of Cajal in canine colonic circular muscle. Anat Embry, 1990;182:215-224
16. Xue C, Ward SM, Shuttleworth CW, Sanders KM. Identification of interstitial cells in canine proximal colon using NADH diaphorase histochemistry. Histochemistry, 1993;99:373-384
17. Anderson CR, Edwards SL. Subunit of cholera toxin labels interstitial cells of Cajal in the gut of rat and mouse. Histochemistry, 1993;100:457-464
18. Hanani M, Louzon V, Miller SM, Faussone-Pellegrini MS. Visualization of interstitial cells of Cajal in the mouse colon by vital staining. Cell Tissue Res, 1998;292: 275-282
19. Hanani M, Belzer V, Rich A, Faussone Faussone-Pellegrini SM. Visualization of interstitial cells of Cajal in living, intact tissues. Microsc Res, 1999;47:336-343
20. Shuttleworth CW, Xue C, Ward SM, de Vente J, Sanders KM. Immunohistochemical localization of 3', 5'-cyclic guanosine monophosphate in the canine proximal colon: responses to nitric oxide and electrical stimulation of enteric inhibitory neurons. Neuroscience, 1993;56:513-522
21. Young HM, McConalogue K, Furness JB, de Vente J. Nitric oxide targets in theguinea-pig intestine identified by induction of cyclic GMP immunoreactivity. Neuroscience, 1993;55:583-596
22. Xue C, Pollock J, Schmidt HHHW, Ward SM, Sanders KM. Expression of nitric oxide synthase by interstitial cells of the canine proximal colon. J Auton Nerv Syst, 1994;49:1-14
23. Christensen J. A commentary on the morphological identification of interstitial cells of Cajal in the gut. J Auton Nerv Syst,1992;37:75-88
24. Shuttleworth CW, Xue C, Ward SM, de Vente J, Sanders KM. Immunohistochemical localization of 3', 5'-cyclicguanosine monophosphate in the canine proximal colon: responses to nitric oxide and electrical stimulation of enteric inhibitory neurons. Neuroscience, 1993;56:513-522
25. Young HM, McConalogue K, Furness JB, de Vente J. Nitric oxide targets in the guinea-pig intestine identified by induction of cyclic GMP immunoreactivity. Neuroscience, 1993;55:583-596
26. Xue C, Pollock J, Schmidt HHHW, Ward SM, Sanders KM. Expression of nitric oxide synthase by interstitial cells of the canine proximal colon. J Auton Nerv Syst, 1994;49:1-14
27. Komuro T, Zhou DS. Anti-c-kit protein immunoreactive cells corresponding to the interstitial cells of Cajal in the guinea-pig small intestine. J Auton Nerv Syst, 1996;61:169-174
28. Burns AJ, Herbert TM, Ward SM, Sanders KM. Interstitial cells of Cajal in the guinea-pig gastrointestinal tract as revealed by c-Kit immunohistochemistry. Cell Tissue Res, 1997;290:11-20
29. Wester T, Eriksson L, Olsson Y, Olsen L. Interstitial cells of Cajal in the human fetal small bowel as shown by c-kit immunohistochemistry. Gut, 1999;44:65-71
30. Kenny SE, Connell G, Woodward MN, Lloyd DA, Gosden CM, Edgar DH, Vaillant C. Ontogeny of interstitial cells of Cajal in the human intestine. J Pediatr Surg, 1999;34:1241-1247
31. Nakagawa T,Misawa H,Nakajima Y,et al.Absence of peristalsis in the ileum of W/W(V) mutant mice that are selectively deficient in myenteric interstitial cells of Cajia. J. Smooth Muscle Res.2005;41:141-151.
32. Sanders KM, Ward SM.Interstitial cells of Cajal: a new perspective on smooth musclefunction.J Physiol. 20061;576(Pt 3):721-726.
33. Sanders KM, Ward SM. Kit mutants and gastrointestinal physiology.J Physiol. 2007;578(Pt 1):33-42.
34. Park SJ,Mckay CM, Zhu Y,Huizinga JD.Volume-activated chloride currents in interstitial cells of Cajal. Am. J. Physiol Gastrointest. Liver Physiol.2005; 289: 791-797
35. Yanagida H, Yanase H, Sanders KM, et al. Intestinal surgical resection disrupts electrical rhythmicity, neural responses, and interstitial cell networks. Gastroenterology. 2004;127(6):1748-1759.
36. Ward SM, Dixon RE, de Faoite A, et al.Voltage-dependent calcium entry underlies propagation of slow waves in canine gastric antrum. J Physiol. 2004;561(Pt 3):793-810.
37. Forrest AS, Ord?g T, Sanders KM.Neural regulation of slow-wave frequency in the murine gastric antrum. Am J Physiol Gastrointest Liver Physiol. 2006; 290 (3):G486-495
38. Megan F. Klemm, Betty Exintaris and R. J. Lang. Identification of the cells underlying pacemaker activity in the guinea-pig upper urinary tract. The Journal of Physiology, 1999, 519(3): 867-884.
39. Lang RJ, Takano H, Davidson ME, et al. Characterization of the spontaneous electrical and contractile activity of smooth muscle cells in the rat upper urinary tract. The Journal of urology, 2001, 166(1):329-334.
40. Pezzone MA., Simon C. Watkins, Sean M. Alber et al. Identification of c-kit-positive cells in the mouse ureter: the interstitial cells of Cajal of the urinary tract. Am J Physiol Renal Physiolv, 2003, 284(5):925-929.
41. Metzger R, Schuster T, Till H, et al. Cajal-like cells in the human upper urinary tract. The journal of urology, 2004,172(2) :769-772.
42. van der AA, F, Roskams T, Blyweert W,et al. Identification fo kit positive cells in the human urinary tract. The journal of urology, 2004, 171(6):2492-2496.
43. Solari V, Piotrowska A, Piaseczna P. Altered Expression of Interstitial Cells of Cajal in Congenital Ureteropelvic Junction Obstruction. The journal of urology, 2003,170(6): 2420-2422.
44. Smet PJ, Jonavicius J, Marshall VR,et,al. Distribution of nitric oxidesynthase-immunoreactive nerves and identification of the cellular targets of nitric oxide in guinea-pig and human urinary bladder by cGMP immunohistochemistry. Neuroscience, 1996, 71(2):337-48.
45. Karen D. McCloskey, Alison M. Gurney Kit positive cells in the guinea pig bladder. J Urol, 2002, 168(2):832-836.
46. 46.A. Shafik Study of the electromechanical activity of the urinary bladder: an experimental study. World J Urol (1994) 12:316-318
47. Piaseczna Piotrowska A, Rolle U, Solari V, et al. Interstitial cells of Cajal in the human normal urinary bladder and in the bladder of patients with megacystis- microcolon intestinal hypoperistalsis syndrome. BJU Int, 2004, 94:143-146.
48. Hashitani H, Fukuta H, Takano H, et al. Origin and propagation of spontaneous excitation in smooth muscle of the guinea-pig urinary bladder. J Physiol, 2001, 530(2):273-286.
49. Piaseczna Piotrowska A, Rolle U, Solari V, et al. Interstitial cells of Cajal in the human normal urinary bladder and in the bladder of patients with megacystis-microcolon intestinal hypoperistalsis syndrome. BJU Int, 2004, 94:143- 146.
50.沈文浩,李为兵,熊恩庆,卢根生,宋波。胃肠道起搏细胞在豚鼠泌尿道分布研究。第三军医大学学报,2006,28(2):172-173.
51. Sergeant GP, Hollywood MA, McCloskey KD, et al. Specialised pacemaking cells in the rabbit urethra. J Physiol, 2000, 526 Pt 2:359 - 366.
52. Van der AA, F, Roskams T, Blyweert W, et al. Identification of kit positive cells in the human urinary tract. The journal of urology, 2004, 171(6):2492-2496.
53. Exintaris B, KlemmMF, Lang RJ. Spontaneous slow wave and contractile activity of the guinea pig prostate. J Urol, 2002, 168(1):315 - 322.
54. Frank Van der AA, Tania Roskams, Wim Blyweert, etal.Interstitial Cells in the Human Prostate: A NewTherapeuticTarget? TheProstate, 2003, 56:250-255.
55. Hikaru Hashitani, Hikaru Suzuki. Identification of interstitial cells of Cajal in corporal tissues of the guinea-pig penis. British Journal of Pharmacology, 2004, 141: 199-204.
56. Sergeant GP, Hollywood MA, McHale NG, Thornbury KD.Ca~(2+) signalling in urethral interstitial cells of Cajal.J Physiol. 2006 Nov 1;576(Pt 3):715-20.
57. Wang XY, Sanders KM, Ward SM. Intimate relationship between interstitial cells of cajal and enteric nerves in the guinea-pig small intestine. Cell Tissue Res 1999; 295: 247-256.
1. Clapper, D. L., Walseth, T. F., Dargie, P. J., & Lee, H. C. (1987). Pyridine nucleotide metabolites stimulate calcium release from sea urchin egg microsomes desensitized to inositol trisphosphate. J Biol Chem 262,9561-9568.
2. Aarhus, R., Graeff, R. M., Dickey, D. M., Walseth, T. F., & Lee, H. C.ADP-ribosyl cyclase and CD38 catalyze the synthesis of a calcium-mobilizing metabolite from NADP. J Biol Chem 270,30327-30333.
3. Galione, A. (1993). Cyclic ADP-ribose: a new way to control calcium.Science 259, 325– 326.
4. Lee, H. C. (1993). Potentiation of calcium- and caffeine-induced calcium release by cyclic ADP-ribose. J Biol Chem 268, 293–299.
5. Yu, J. Z., Zhang, D. X., Zou, A. P., Campbell, W. B., & Li, P. L. (2000).Nitric oxide inhibits Ca(2+) mobilization through cADP-ribose signaling in coronary arterial smooth muscle cells. Am J Physiol Heart Circ Physiol 279, H873-H881.
6. Lee, H. C., Walseth, T. F., Bratt, G. T., Hayes, R. N., & Clapper, D. L.(1989). Structural determination of a cyclic metabolite of NAD+ with intracellular Ca~(2+)-mobilizing activity. J Biol Chem 264, 1608–1615.
7. Lee, H. C., & Aarhus, R. (1991). ADP-ribosyl cyclase: an enzyme that cyclizes NAD+ into a calcium-mobilizing metabolite. Cell Regul 2,203– 209.
8. Rusinko, N., & Lee, H. C. (1989). Widespread occurrence in animal tissues of an enzyme catalyzing the conversion of NAD+ into a cyclic N. Bai et al. / Pharmacology & Therapeutics 105 (2005) 189–207 205 metabolite with intracellular Ca~(2+)-mobilizing activity. J Biol Chem 264,11725-11731.
9. Lee, H. C. (1996). Modulator and messenger functions of cyclic ADPribose in calcium signaling. Recent Prog Horm Res 51, 355–388.
10. Mitsui-Saito, M., Kato, I., Takasawa, S., Okamoto, H., & Yanagisawa, T.(2003). CD38 gene disruption inhibits the contraction induced byalpha-adrenoceptor stimulation in mouse aorta. J Vet Med Sci 65,1325-1330.
11. Cheung, D. W. (2003). Modulation of spontaneous transient Ca~(2+)-activated K+ channel currents by cADP-ribose in vascular smooth muscle cells.Eur J Pharmacol 458, 57– 59.
12. Y.X. Wang, Y.M. Zheng, Q.B. Mei, et al., FKBP12,6 and cADPR regulation of Ca~(2+) release in smooth muscle cells, Am. J. Physiol.Cell Physiol. 286 (2004) C538–C546.
13. Y.S. Prakash, M.S. Kannan, T.F. Walseth, G.C. Sieck, Role of cyclic ADP-ribose in the regulation of [Ca~(2+)]i in porcine tracheal smooth muscle, Am. J. Physiol. 274 (1998) C1653–C1660.
14. A.J. Lokuta, A. Darszon, C. Beltran, H.H. Valdivia, Detection and functional characterization of ryanodine receptors from sea urchin eggs, J. Physiol. 510 (1998) 155–164.
15. C.F. Perez, J.J. Marengo, R. Bull, C. Hidalgo, Cyclic ADP-ribose activates caffeine-sensitive calcium channels from sea urchin egg microsomes, Am. J. Physiol. 274 (1998) C430–C439.
16. L.G. Meszaros, J. Bak, A. Chu, Cyclic ADP-ribose as an endogenous regulator of the non-skeletal type ryanodine receptor Ca~(2+) channel,Nature 364 (1993) 76–79.
17. R. Sitsapesan, S.J. McGarry, A.J. Williams, Cyclic ADP-ribose, the ryanodine receptor and Ca~(2+) release, Trends Pharmacol. Sci. 16(1995) 386–391.
18. B.R. Fruen, J.R. Mickelson, N.H. Shomer, P.Velez, C.F. Louis, Cyclic ADP-ribose does not affect cardiac or skeletal muscle ryanodine receptors, FEBS Lett. 352 (1994) 123–126.
19. A.M. Evans, C.N.Wyatt, N.P. Kinnear, J.H. Clark, E.A. Blanco, Pyridine nucleotides and calcium signalling in arterial smooth muscle:from cell physiology to pharmacology, Pharmacol. Ther. 107 (2005)286–313.
20. J.M. Thomas, R. Masgrau, G.C. Churchill, A. Galione, Pharmacological characterization of the putative cADP-ribose receptor, Biochem.J. 359 (2001) 451– 457.
21. T.F. Walseth, R. Aarhus, J.A. Kerr, H.C. Lee, Identification of cyclic ADP-ribose- binding proteins by photoaffinity labeling, J. Biol. Chem.268 (1993) 26686–26691.
22. C. Franzini-Armstrong, F. Protasi, Ryanodine receptors of striated muscles: a complex channel capable of multiple interactions, Physiol.Rev. 77 (1997) 699-729.
23. M.G. Chelu, C.I. Danila, C.P. Gilman, S.L. Hamilton, Regulation of ryanodine receptors by FK506 binding proteins, Trends Cardiovasc.Med. 14 (2004) 227–234.
24. N. Noguchi, S. Takasawa, K. Nata, et al., Cyclic ADP-ribose binds to FK506-binding protein 12.6 to release Ca~(2+) from islet microsomes,J. Biol. Chem. 272 (1997) 3133–3136.
25. K.N. Bradley, S. Currie, D. MacMillan, T.C. Muir, J.G. McCarron,Cyclic ADP-ribose increases Ca~(2+) removal in smooth muscle, J. Cell Sci. 116 (2003) 4291–4306.
26. J.A. Copello, Y. Qi, L.H. Jeyakumar, E. Ogunbunmi, S. Fleischer,Lack of effect of cADP-ribose and NAADP on the activity of skeletal muscle and heart ryanodine receptors, Cell Calcium 30 (2001)269-284.
27. G. Bultynck, P. De Smet, D. Rossi, et al., Characterization and mapping of the 12 kDa FK506-binding protein (FKBP12)—binding site on different isoforms of the ryanodine receptor and of the inositol 1,4,5-trisphosphate receptor, Biochem. J. 354 (2001) 413–422.
28. W.X. Tang, Y.F. Chen, A.P. Zou, W.B. Campbell, P.L. Li, Role of FKBP12.6 incADPR-induced activation of reconstituted ryanodine receptors from arterial smooth muscle, Am. J. Physiol. Heart Circ.Physiol. 282 (2002) H1304–H1310.
29. G. Bultynck, D. Rossi, G. Callewaert, et al., The conserved sites for the FK506- binding proteins in ryanodine receptors and inositol 1,4,5-trisphosphate receptors are structurally and functionally different, J.Biol. Chem. 276 (2001) 47715–47724.
30. E.D. Moore, T. Voigt, Y.M. Kobayashi, et al., Organization of Ca~(2+) release units in excitable smooth muscle of the guinea-pig urinarybladder, Biophys. J. 87 (2004) 1836–1847.
31. H.J. Schatzmann, The calcium pump of the surface membrane and ofthe sarcoplasmic reticulum, Annu. Rev. Physiol. 51 (1989) 473–485.
32. Lukyanenko, V., Gyorke, I., Wiesner, T. F., & Gyorke, S. (2001).Potentiation of Ca(2+) release by cADP-ribose in the heart is mediated by enhanced SR Ca(2+) uptake into the sarcoplasmic reticulum. Circ Res 89, 614–622.
33. Rakovic, S., & Terrar, D. A. (2002). Terrar. Calcium signaling by cADPR in cardiac myocytes. In H. C. Lee (Ed.), Cyclic ADP-ribose and NAADP.Structures, Metabolism and Functions (pp. 331– 333). Dordrecht Kluwer Academic Publishing.
34. Itoh, M., Ishihara, K., Tomizawa, H., Tanaka, H., Kobune, Y., Ishikawa, J.,et al. (1994). Molecular cloning of murine BST-1 having homology with CD38 and Aplysia ADP-ribosyl cyclase. Biochem Biophys Res Commun 203, 1309– 1317.
35. Collier, M. L., Ji, G., Wang, Y., & Kotlikoff, M. I. (2000). Calcium-induced calcium release in smooth muscle: loose coupling between the action potential and calcium release. J Gen Physiol 115, 653–662.
36. Zhang, A. Y., Yi, F., Teggatz, E. G., Zou, A. P., & Li, P. L. (2004).Enhanced production and action of cyclic ADP-ribose during oxidative stress in small bovine coronary arterial smooth muscle. Microvasc Res 67, 159–167.
37. Katsuyama, H., Ito, S., Itoh, T., & Kuriyama, H. (1991). Effects of ryanodine on acetylcholine-induced Ca~(2+) mobilization in single smooth muscle cells of the porcine coronary artery. Pflugers Arch 419, 460-466.
38. Geiger, J., Zou, A. P., Campbell, W. B., & Li, P. L. (2000). Inhibition of cADP-ribose formation produces vasodilation in bovine coronary arteries. Hypertension 35, 397-402.
39. Kuemmerle, J. F., & Makhlouf, G. M. (1995). Agonist-stimulated cyclic ADP ribose. Endogenous modulator of Ca~(2+)-induced Ca~(2+) release in intestinal longitudinal muscle. J Biol Chem 270, 25488–25494.
40. Higashida, H., Yokoyama, S., Hashii, M., Taketo, M., Higashida, M.,Takayasu, T., et al. (1997). Muscarinic receptor-mediated dual regulation of ADP-ribosyl cyclase in NG108-15 neuronal cell membranes.J Biol Chem 272, 31272–31277.
41. Prakash, Y. S., Kannan, M. S., Walseth, T. F., & Sieck, G. C. (1998). Roleof cyclic ADP-ribose in the regulation of [Ca~(2+)]i in porcine tracheal smooth muscle. Am J Physiol 274, C1653-C1660.
42. Ge, Z. D., Zhang, D. X., Chen, Y. F., Yi, F. X., Zou, A. P., Campbell, W. B.,et al. (2003). Cyclic ADP-ribose contributes to contraction and Ca~(2+) release by M1 muscarinic receptor activation in coronary arterial smooth muscle. J Vasc Res 40, 28– 36.
43. Bailey, V. C., Sethi, J. K., Fortt, S. M., Galione, A., & Potter, B. V. (1997).7-Deaza cyclic adenosine 5V-diphosphate ribose: first example of a Ca~(2+)-mobilizing partial agonist related to cyclic adenosine 5V-diphosphate ribose. Chem Biol 4, 51-61.
44. Li, P. L., Zou, A. P., & Campbell, W. B. (1998b). Regulation of KCachannel activity by cyclic ADP-ribose and ADP-ribose in coronary arterial smooth muscle. Am J Physiol 275, H1002– H1010.
45. Bailey, V. C., Sethi, J. K., Fortt, S. M., Galione, A., & Potter, B. V. (1997).7-Deaza cyclic adenosine 5V-diphosphate ribose: first example of a Ca~(2+)-mobilizing partial agonist related to cyclic adenosine 5V-diphosphate ribose. Chem Biol 4, 51-61.
46. Campbell, W. B., Gebremedhin, D., Pratt, P. F., & Harder, D. R. (1996).Identification of epoxyeicosatrienoic acids as endothelium-derived hyperpolarizing factors. Circ Res 78, 415-423.
47. Li, P. L., Zhang, D. X., Ge, Z. D., & Campbell,W. B. (2002). Role of ADPribose in 11,12-EET-induced activation of K(Ca) channels in coronary arterial smooth muscle cells. Am J Physiol Heart Circ Physiol 282,H1229-H1236.
48. Wellman, G. C., Santana, L. F., Bonev, A. D., & Nelson, M. T. (2001). Role of phospholamban in the modulation of arterial Ca(2+) sparks and Ca(2+)-activated K(+) channels by cAMP. Am J Physiol Cell Physiol 28, C1029-C1037.
49. Boittin, F. X., Dipp, M., Kinnear, N. P., Galione, A., & Evans, A. M. (2003).Vasodilation by the calcium-mobilizing messenger cyclic ADPribose.J Biol Chem 278, 9602– 9608.
50. Kannan, M. S., Prakash, Y. S., Johnson, D. E., & Sieck, G. C. (1997b).Nitric oxide inhibits calcium release from sarcoplasmic reticulum of porcine tracheal smooth muscle cells. Am J Physiol 272, L1-L7.
51. White, T. A., Walseth, T. F., & Kannan, M. S. (2002). Nitric oxide inhibits ADP-ribosyl cyclase through a cGMP-independent pathway in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 283,L1065-L1071.
52. Wellman, G. C., Santana, L. F., Bonev, A. D., & Nelson, M. T. (2001). Role of phospholamban in the modulation of arterial Ca(2+) sparks and Ca(2+)-activated K(+) channels by cAMP. Am J Physiol Cell Physiol 28, C1029–C1037.
53. Fuchs, A. R. (1995). Plasma, membrane receptors regulating myometrial contractility and their hormonal modulation. Semin Perinatol 19,15-30.
54. Sanborn, B. M., Qian, A., Ku, C. Y., Wen, Y., Anwer, K., Monga, M., et al.(1995). Mechanisms regulating oxytocin receptor coupling to phospholipase C in rat and human myometrium. Adv Exp Med Biol 39, 469-479.
55. Berridge, M. J. (1993). Inositol trisphosphate and calcium signalling.Nature 361, 315–325.
56. Lynn, S., Morgan, J. M., Lamb, H. K., Meissner, G., & Gillespie, J. I.(1995). Isolation and partial cloning of ryanodine-sensitive Ca~(2+) release channel protein isoforms from human myometrial smooth muscle.FEBS Lett 18, 6-12.
57. Chini, E. N., de Toledo, F. G., Thompson, M. A., & Dousa, T. P. (1997).Effect of estrogen upon cyclic ADP ribose metabolism: beta-estradiol stimulates ADP ribosyl cyclase in rat uterus. Proc Natl Acad Sci USA 94, 5872-5876.
58. Wu, X., Pang, S. T., Sahlin, L., Blanck, A., Norstedt, G., & Flores-Morales,A. (2003). Gene expression profiling of the effects of castration and estrogen treatment in the rat uterus. Biol Reprod 69, 1308-1317.
59. Blatter, L. A., & Wier, W. G. (1994). Nitric oxide decreases [Ca~(2+)]_i in vascular smooth muscle by inhibition of the calcium current. Cell Calcium 15, 122-131.
60. Dogan, S., Deshpande, D. A., Kannan, M. S., & Walseth, T. F. (2004).Changes in CD38 expression and ADP-ribosyl cyclase activity in rat myometrium duringpregnancy: influence of sex steroid hormones. Biol Reprod 71, 97-103.
61. Chini, E. N., de Toledo, F. G., Thompson, M. A., & Dousa, T. P. (1997).Effect of estrogen upon cyclic ADP ribose metabolism: beta-estradiol stimulates ADP ribosyl cyclase in rat uterus. Proc Natl Acad Sci USA 94, 5872– 5876.
62. Chini, E. N., Chini, C. C., Barata da Silva, S., & Zielinska, W. (2002). The cyclic-ADP-ribose signaling pathway in human myometrium. Arch Biochem Biophys 407, 152–159.
63. Dogan, S., White, T. A., Deshpande, D. A., Murtaugh, M. P., Walseth, T. F., & Kannan, M. S. (2002). Estrogen increases CD38 gene expression and leads to differential regulation of adenosine diphosphate (ADP)-ribosyl cyclase and cyclic ADP-ribose hydrolase activities in rat myometrium.Biol Reprod 66, 596-602.
64. Hardingham, G. E., Chawla, S., Johnson, C. M., & Bading, H. (1997).Distinct functions of nuclear and cytoplasmic calcium in the control of gene expression. Nature 385, 260-265.
65. Romanini, C. (1994). In T. Chard, & J. G. Grudzinskas (Eds.), The Uterus(pp. 337– 355). Cambridge7 Cambridge Univ. Press.
66. Tliba, O., Panettieri Jr., R. A., Tliba, S., Walseth, T. F., & Amrani, Y.(2004). Tumor necrosis factor-{alpha} differentially regulates the expression of proinflammatory genes in human airway smooth muscle cells by activation of interferon-{beta}- dependent CD38 pathway. Mol Pharmacol 66, 322– 329.
67. Deshpande, D. A., Dogan, S., Walseth, T. F., Miller, S. M., Amrani, Y.,Panettieri, R. A., et al. (2004). Modulation of calcium signaling by interleukin-13 in human airway smooth muscle: role of CD38/cyclic adenosine diphosphate ribose pathway. Am J Respir Cell Mol Biol 31,36-42.
68. Chidambaram, N., Wong, E. T., & Chang, C. F. (1998).Differentialoligomerization of membrane-bound CD38/ADP-ribosyl cyclase in porcine heart microsomes. Biochem Mol Biol Int 44, 1225-1233.