大鼠胰岛β细胞P糖蛋白的表达及功能研究
|
摘要
目的早期研究显示在小鼠胰岛B细胞中有一种与P糖蛋白(也称为多药耐药蛋白1, Multidrug Resistantance Protein 1, MDR1)相似的65kDa大小的膜蛋白,且借助膜片钳技术发现此蛋白有类似磺脲类受体的功能,可促进胰岛素颗粒释放。本课题目的首先探测大鼠胰岛β细胞中mini-P糖蛋白存在的可能性,并使用拮抗剂及RNA干扰技术进行该蛋白的功能研究,分析其在胰岛素两相分泌中的作用。
方法(1)经胆管不离体灌注胶原酶V消化分离Wistar大鼠胰岛；INS-1细胞培养。分别提取大鼠胰岛、胰腺及INS-1细胞中的总RNA,针对MDR1特异基因序列abcblb的3'末端及5'末端设计多对引物,进行RT-PCR;萃取大鼠胰岛及INS-1细胞蛋白,以MDR1特异性抗体(C219)进行免疫印迹实验厂探测目的蛋白的存在。(2)针对P糖蛋白特异基因序列(abcblb)设计寡核苷酸序列,使用siRNA干扰技术孵育胰岛；转染效率的观察分别采用荧光显微镜观察,real-time PCR法测定目的基因的表达量及Western Blot去测定蛋白表达量的变化；进行葡萄糖刺激的胰岛素释放实验,采用放免法测定RNA干扰后大鼠胰岛的胰岛素两相分泌的变化。(3)建立高糖培养大鼠胰岛凋亡的模型,采用real-time PCR法测定siRNA干扰后,凋亡基因表达的变化,评价RNA干扰对于胰岛凋亡的影响,进一步分析目的蛋白在胰岛素两相分泌中的作用。(4)使用MDR1特异性拮抗剂(环孢菌素A)干预大鼠胰岛,放免法测定胰岛素的两相分泌。
结果(1)RT-PCR实验提取的大鼠胰岛、胰腺及INS-1细胞中均扩增出了相应的目的片段,且在胰岛中的表达量较胰腺及INS-1细胞中表达量大。免疫印迹实验中,使用C219在胰岛匀浆蛋白中探测到65kDa大小的蛋白,在INS-1细胞蛋白萃取液中探测到了160kDa大小的蛋白。(2)在RNA干扰实验中,转染后48小时的胰岛于荧光显微镜下观察可见90%的胰岛均呈现红色荧光,提示转染成功；Western Blot实验结果提示在空白组、实验组及阴性对照组,使用C219均探测到了65kDa大小的蛋白,且实验组较空白组及阴性对照组蛋白表达量下调,而空白组及阴性对照无明显变化；siRNA干扰后abcblb基因的表达量实验组的较阴性及空白组减少,阴性组及空白组两组无变化；与abcblb基因相似的abcbla基因的表达量在三组中无变化,胰岛素合成相关基因insuin1、insulin2及胰高血糖素合成基因glucagon表达量无变化；siRNA干扰后,三组胰岛素分泌均呈现两相分泌,实验组的胰岛素一相及二相分泌较空白组及阴性对照组均受损。(3)高糖孵育后高糖组casp3及bax基因的表达量较正常组上调,高糖组Bcl-2基因的表达量较正常组下调,而Bcl-xl基因在两组中表达无差异；siRNA干扰后casp3 bax Bcl-2及Bcl-xl基因表达量在实验组、阴性对照组及空白组中的表达量均无变化。(4)在体外胰岛刺激实验中,MDR1拮抗剂环孢菌素A,抑制了胰岛素第二时相分泌,但胰岛素第一时相分泌无明显变化。
结论(1)在INS-1细胞中有全长的P糖蛋白的表达,在大鼠胰岛中有mini-P糖蛋白的表达。P糖蛋白的表达不同,提示着二者可能具有不同的生物学功能。在INS-1细胞中,P糖蛋白可能主要与耐药相关,而在胰岛细胞中,mini的P糖蛋白可能主要与胰岛素的分泌释放相关。(2)siRNA干扰后,目的基因abcb16表达量下调,胰岛素的两相分泌均受损,而凋亡相关基因及胰岛素合成相关基因的表达无改变,提示siRNA干扰后未直接影响胰岛素的合成,且胰岛素的两相分泌受损并非通过凋亡途径,进一步支持了前述观点,P糖蛋白或mini-P糖蛋白影响胰岛素颗粒的酸化成熟,调节胰岛素的两相分泌。(3)使用环孢菌素A干预胰岛后,胰岛素的一相分泌未受影响,而胰岛素的二相分泌明显受抑制,推测其拮抗P糖蛋白或mini-P糖蛋白,从而影响胰岛素颗粒的酸化成熟,表现为胰岛素的二相分泌受损。(4)深入研究mini-P糖蛋白的结构及功能,可为新的降糖药物的研发提供理论基础,为糖尿病的治疗提供新思路。
Objective A 65-kda mdrl (multi-drug resistance protein 1, P-glycoprotein)-like protein has been suggested to be a regulatory protein to chloride channel protein 3 (C1C-3) mediating insulin granules acidification and release in mouse beta cells. But the protein has not been deeply investigated. In this study, we identified existence of the 65-kda protein in rat islets and preliminarily explored its biological functions.
Methods (1) Rat pancreas were digested by collagenase V through bile-duct injection and islets were isolated manually. A insulinoma cells (INS-1) were cultured. Total RNAs of the rat kidneys served as positive controls, pancreata, islets and INS-1 cells were extracted for reverse transcript PCR (RT-PCR), respectively. The cDNAs were run with specific primers selected from the mRNA of abcb1b encoding P-glycoprotein. All PCR products were visualized in agarose gel electrophoresis and sequenced. Homogenates of rat islets and INS-1 cells were applied to SDS-PAGE. P-glycoprotein was detected by a specific monoclonal antibody (C219). (2) Rat Islets were incubated with designed siRNAs to down-regulate expression of the abcb1b gene. Transfection efficiency was evaluated by fluorescence microscope, quantitative PCR and western blot. The transfected islets were incubated with high glucose (16.7mM) buffer and biphasic insulin release was measured by radioimmunology (RIA) assay. Meanwile the expression of ins1, ins2 and glucagon were also determined by quantitative PCR (3) Rat islets were incubated in RPMI1640 (with 33.3mM glucose) for 48 hours to induce apoptosis. The apoptosis were assessed both in the silenced islets and in the islets incubated with the 33.3mM glucose media by quantitative PCR. (4) Rat islets were treated by cyclosporine which is a specific inhibitor to P-glycoprotein. Comparison of insuling release between the treated islets and non-treated islets was carried out by RIA.
Results (1) Compared with the positive control, expression of the P-glycoprotein mRNA segments were detected in the islets, INS-1 cells and pancreas. Sequence analysis confirmed the PCR products were matched with mRNA of P-glycoprotein. In western blot, a 65-kda protein was recognized by the antibody in the islets homogenate but not in that of INS-1 cells. Instead, the homogenate of INS-1 cells contained a 160-kda protein recognized by the antibody. (2)90% islets showed red-fluorescence 48 hours after the oligonucleotides (the silencers to the abc1b1 and the control oligonucleotides) transfection. The expression of 65kDa protein and the mRNA of abcb1b were down-regulated in the silenced islets. All of them suggested the RNAi was successful. Insulin secretion of rat islets stimulated by high glucose (16.7mM) showed biphasic curve during 60-min incubation. After the RNAi, both the first and the second phase of insulin secretion was reduced significantly. The expression of insl, ins2 and glucagon were not interfered with the RNAi. (3) Several key genes mediating apoptosis did not show any differences between pre and post-RNAi in the rat islets, whereas the apoptosis genes were changed significantly by the high glucose incubation accordingly. (4) After incubation with cyclosporine A, the second phase of insulin secretion was reduced significantly but the first phase was not influenced.
Conclusion The 65-kda protein expressed in rat islets is most likely a mini-P-glycoprotein. It may play a key role regulating biphasic insulin release. The regulation may not induce by apoptosis or insulin synthesis. It might regulate the insulin granule acidification and the priming. Characterization of the structures and functions of the mini-P-glycoprotein may provide potentials to develop new anti-diabetic drugs.
方法(1)经胆管不离体灌注胶原酶V消化分离Wistar大鼠胰岛；INS-1细胞培养。分别提取大鼠胰岛、胰腺及INS-1细胞中的总RNA,针对MDR1特异基因序列abcblb的3'末端及5'末端设计多对引物,进行RT-PCR;萃取大鼠胰岛及INS-1细胞蛋白,以MDR1特异性抗体(C219)进行免疫印迹实验厂探测目的蛋白的存在。(2)针对P糖蛋白特异基因序列(abcblb)设计寡核苷酸序列,使用siRNA干扰技术孵育胰岛；转染效率的观察分别采用荧光显微镜观察,real-time PCR法测定目的基因的表达量及Western Blot去测定蛋白表达量的变化；进行葡萄糖刺激的胰岛素释放实验,采用放免法测定RNA干扰后大鼠胰岛的胰岛素两相分泌的变化。(3)建立高糖培养大鼠胰岛凋亡的模型,采用real-time PCR法测定siRNA干扰后,凋亡基因表达的变化,评价RNA干扰对于胰岛凋亡的影响,进一步分析目的蛋白在胰岛素两相分泌中的作用。(4)使用MDR1特异性拮抗剂(环孢菌素A)干预大鼠胰岛,放免法测定胰岛素的两相分泌。
结果(1)RT-PCR实验提取的大鼠胰岛、胰腺及INS-1细胞中均扩增出了相应的目的片段,且在胰岛中的表达量较胰腺及INS-1细胞中表达量大。免疫印迹实验中,使用C219在胰岛匀浆蛋白中探测到65kDa大小的蛋白,在INS-1细胞蛋白萃取液中探测到了160kDa大小的蛋白。(2)在RNA干扰实验中,转染后48小时的胰岛于荧光显微镜下观察可见90%的胰岛均呈现红色荧光,提示转染成功；Western Blot实验结果提示在空白组、实验组及阴性对照组,使用C219均探测到了65kDa大小的蛋白,且实验组较空白组及阴性对照组蛋白表达量下调,而空白组及阴性对照无明显变化；siRNA干扰后abcblb基因的表达量实验组的较阴性及空白组减少,阴性组及空白组两组无变化；与abcblb基因相似的abcbla基因的表达量在三组中无变化,胰岛素合成相关基因insuin1、insulin2及胰高血糖素合成基因glucagon表达量无变化；siRNA干扰后,三组胰岛素分泌均呈现两相分泌,实验组的胰岛素一相及二相分泌较空白组及阴性对照组均受损。(3)高糖孵育后高糖组casp3及bax基因的表达量较正常组上调,高糖组Bcl-2基因的表达量较正常组下调,而Bcl-xl基因在两组中表达无差异；siRNA干扰后casp3 bax Bcl-2及Bcl-xl基因表达量在实验组、阴性对照组及空白组中的表达量均无变化。(4)在体外胰岛刺激实验中,MDR1拮抗剂环孢菌素A,抑制了胰岛素第二时相分泌,但胰岛素第一时相分泌无明显变化。
结论(1)在INS-1细胞中有全长的P糖蛋白的表达,在大鼠胰岛中有mini-P糖蛋白的表达。P糖蛋白的表达不同,提示着二者可能具有不同的生物学功能。在INS-1细胞中,P糖蛋白可能主要与耐药相关,而在胰岛细胞中,mini的P糖蛋白可能主要与胰岛素的分泌释放相关。(2)siRNA干扰后,目的基因abcb16表达量下调,胰岛素的两相分泌均受损,而凋亡相关基因及胰岛素合成相关基因的表达无改变,提示siRNA干扰后未直接影响胰岛素的合成,且胰岛素的两相分泌受损并非通过凋亡途径,进一步支持了前述观点,P糖蛋白或mini-P糖蛋白影响胰岛素颗粒的酸化成熟,调节胰岛素的两相分泌。(3)使用环孢菌素A干预胰岛后,胰岛素的一相分泌未受影响,而胰岛素的二相分泌明显受抑制,推测其拮抗P糖蛋白或mini-P糖蛋白,从而影响胰岛素颗粒的酸化成熟,表现为胰岛素的二相分泌受损。(4)深入研究mini-P糖蛋白的结构及功能,可为新的降糖药物的研发提供理论基础,为糖尿病的治疗提供新思路。
Objective A 65-kda mdrl (multi-drug resistance protein 1, P-glycoprotein)-like protein has been suggested to be a regulatory protein to chloride channel protein 3 (C1C-3) mediating insulin granules acidification and release in mouse beta cells. But the protein has not been deeply investigated. In this study, we identified existence of the 65-kda protein in rat islets and preliminarily explored its biological functions.
Methods (1) Rat pancreas were digested by collagenase V through bile-duct injection and islets were isolated manually. A insulinoma cells (INS-1) were cultured. Total RNAs of the rat kidneys served as positive controls, pancreata, islets and INS-1 cells were extracted for reverse transcript PCR (RT-PCR), respectively. The cDNAs were run with specific primers selected from the mRNA of abcb1b encoding P-glycoprotein. All PCR products were visualized in agarose gel electrophoresis and sequenced. Homogenates of rat islets and INS-1 cells were applied to SDS-PAGE. P-glycoprotein was detected by a specific monoclonal antibody (C219). (2) Rat Islets were incubated with designed siRNAs to down-regulate expression of the abcb1b gene. Transfection efficiency was evaluated by fluorescence microscope, quantitative PCR and western blot. The transfected islets were incubated with high glucose (16.7mM) buffer and biphasic insulin release was measured by radioimmunology (RIA) assay. Meanwile the expression of ins1, ins2 and glucagon were also determined by quantitative PCR (3) Rat islets were incubated in RPMI1640 (with 33.3mM glucose) for 48 hours to induce apoptosis. The apoptosis were assessed both in the silenced islets and in the islets incubated with the 33.3mM glucose media by quantitative PCR. (4) Rat islets were treated by cyclosporine which is a specific inhibitor to P-glycoprotein. Comparison of insuling release between the treated islets and non-treated islets was carried out by RIA.
Results (1) Compared with the positive control, expression of the P-glycoprotein mRNA segments were detected in the islets, INS-1 cells and pancreas. Sequence analysis confirmed the PCR products were matched with mRNA of P-glycoprotein. In western blot, a 65-kda protein was recognized by the antibody in the islets homogenate but not in that of INS-1 cells. Instead, the homogenate of INS-1 cells contained a 160-kda protein recognized by the antibody. (2)90% islets showed red-fluorescence 48 hours after the oligonucleotides (the silencers to the abc1b1 and the control oligonucleotides) transfection. The expression of 65kDa protein and the mRNA of abcb1b were down-regulated in the silenced islets. All of them suggested the RNAi was successful. Insulin secretion of rat islets stimulated by high glucose (16.7mM) showed biphasic curve during 60-min incubation. After the RNAi, both the first and the second phase of insulin secretion was reduced significantly. The expression of insl, ins2 and glucagon were not interfered with the RNAi. (3) Several key genes mediating apoptosis did not show any differences between pre and post-RNAi in the rat islets, whereas the apoptosis genes were changed significantly by the high glucose incubation accordingly. (4) After incubation with cyclosporine A, the second phase of insulin secretion was reduced significantly but the first phase was not influenced.
Conclusion The 65-kda protein expressed in rat islets is most likely a mini-P-glycoprotein. It may play a key role regulating biphasic insulin release. The regulation may not induce by apoptosis or insulin synthesis. It might regulate the insulin granule acidification and the priming. Characterization of the structures and functions of the mini-P-glycoprotein may provide potentials to develop new anti-diabetic drugs.
引文
[1]Tzoulaki I, Molokhia M, Curcin V, et al. Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs:retrospective cohort study using UK general practice research database [J]. BMJ,2009,339:b4731.
[2]Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones:a meta-analysis of randomized clinical trials [J]. Lancet,2007,370:1129-36.
[3]Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes [J]. N Engl J Med,2007, 356:2457-71.
[4]Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD):a multicentre, randomised, open-label trial [J]. Lancet,2009, 373:2125-35.
[5]Diamond GA, Bax L, Kaul S. Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death [J]. Ann Intern Med, 2007,147:578-81.
[6]Lincoff AM, Wolski K, Nicholls SJ, et al. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus:a meta-analysis of randomized trials [J]. JAMA,2007,298:1180-8.
[7]Lipscombe LL, Gomes T, Levesque LE, et al. Thiazolidinediones and cardiovascular outcomes in older patients with diabetes [J]. JAMA,2007, 298:2634-43.
[8]Evans J, Ogston S, Emslie-Smith A, Morris A. Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes:a comparison of patients treatedwith sulphonylureas andmetformin. Diabetologia 2006; 49:930-6.
[9]Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes [J]. N Engl J Med,2008, 358:2545-59.
[10]ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes [J]. N Engl J Med,2008,358:2560-72.
[11]中华医学会糖尿病学分会.《中国2型糖尿病防治指南》(试行本)(节选)[J].中国慢性病预防与控制,2004,126：283-5.
[12]Yi Lin, Zhongjie Sun. Current views on type 2 diabetes [J]. Journal of Endocrinology,2010,204:1-11.
[13]Das SK, Elbein SC. The genetic basis of type 2 diabetes [J]. Cell science,2006, 2:100-31.
[14]Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes:principles of pathogenesis and therapy [J]. Lancet,2005,365:1333-46.
[15]DeFronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of NIDDM. A balanced overview [J]. Diabetes Care,1992,15:318-68.
[16]Hou JC, Min L, Pessin JE. Insulin granule biogenesis, trafficking and exocytosis [J]. Vitam Horm,2009,80:473-506.
[17]Del Prato S, Marchetti P, Bonadonna RC. Phasic insulin release and metabolic regulation in type 2 diabetes [J]. Diabetes,2002,51:S109-16.
[18]Barg S, Lindqvist A, Obermuller S. Granule docking and cargo release in pancreatic beta-cells [J]. Biochem Soc Trans,2008,36(pt 3):294-9.
[19]Barg S, Huang P, Eliasson L, et al. Priming of insulin granules for exocytosis by granular Cl(-) uptake and acidification [J]. J Cell Sci,2001,114:2145-54.
[20]Michael A. Burke, R. Kannan Mutharasan, et al. The Sulfonylurea Receptor, an Atypical ATP-Binding Cassette Protein, and Its Regulation of the KATP Channel [J]. Circ Res,2008,102:164-76.
[21]Rees DC, Johnson E, Lewinson O. ABC transporters:the power to change [J]. Nature Reviews Molecular Cell Biology,2009,10:218-27.
[22]Sebastian Barg, Erik Renstrom, Per-Olof Berggren, et al. The stimulatory action of tolbutamide on Ca2+-dependent exocytosis in pancreatic b cells is mediated by a 65-kDa mdr-like P-glycoprotein [J]. Proc. Natl. Acad. Sci,1999,96:5539-44.
[23]Thevenod F. Ion channels in secretory granules of the pancreas and their role in exocytosis and release of secretory proteins [J]. Am J Physiol Cell Physiol,2002, 283:C651-672.
[24]Gotoh M, Maki T, Kiyoizumi T, et al. An improved method for isolation of mouse panreatic islets [J]. Transplantation,1985,40:437-8.
[25]Straub SG, Sharp GW. Glucose-stimulated signaling pathways in biphasic insulin secretion [J]. Diabetes Metab Res Rev,2002,18(6):451-63.
[26]Del Prato S. Loss of early insulin secretion leads to postprandial hyperglycaemia [J]. Diabetologia,2003,46 Suppl 1:M2-8.
[27]Rorsman P, Eliasson L, Renstrom E, et al. The Cell Physiology of Biphasic Insulin Secretion [J]. News Physiol Sci,2000,15:72-7.
[28]Straub S, Shanmugam G, Sharp G.. Stimulation of insulin release by glucose is associated with an increase in the number of docked granules in the β-cells of rat pancreatic islets [J]. Diabetes,2004,53:3179-83.
[29]Ohara-Imaizumi M. Imaging analysis reveals mechanistic differences between first- and second-phase insulin exocytosis [J]. J Cell Biol,2007,177:695-705.
[30]Merrins MJ, Stuenkel EL. Kinetics of Rab27a-dependent actions on vesicle docking and priming in pancreatic beta-cells [J].J Physiol.,2008,586(Pt 22):5367-81.
[31]Vikman J, Ma X, Hockerman GH, et al. Antibody inhibition of synaptosomal protein of 25 kDa (SNAP-25) and syntaxin 1 reduces rapid exocytosis in insulin-secreting cells [J]. J Mol Endocrinol,2006,36(3):503-15.
[32]Barg S, Eliasson L, Renstrom E, et al. A subset of 50 secretory granules in close contact with L-type Ca2+ channels accounts for first-phase insulin secretion in mouse beta-cells [J].Diabetes,2002,51 Suppl 1:S74-82.
[33]Renstrom E, Eliasson L, Bokvist K, et al. Cooling inhibits exocytosis in single mouse pancreatic B-cells by suppression of granule mobilization [J]. J Physiol, 1996,494 (Pt 1):41-52.
[34]Sweet IR, Gilbert M. Contribution of calcium influx in mediating glucose-stimulated oxygen consumption in pancreatic islets [J]. Diabetes,2006, 55(12):3509-19.
[35]Wang Z, Thurmond DC. Mechanisms of biphasic insulin-granule exocytosis-roles of the cytoskeleton, small GTPases and SNARE proteins [J]. J Cell Sci, 2009,122(Pt 7):893-903.
[36]Oh E, Thurmond DC. Muncl8c depletion selectively impairs the sustained phase of insulin release [J].Diabetes,2009,58(5):1165-74.
[37]Joost HG, Bell GI, Best JD, et al. Nomenclature of the GLUT/SLC2A family of sugar/polyol transport facilitators [J]. American Journal of Physiology Endocrinology and Metabolism,2002,282:E974-E976.
[38]BjornholmM, Zierath JR. Insulin signal transduction in human skeletal muscle: identifying the defects in type Ⅱ diabetes [J]. Biochemical Society Transactions, 2005,33:354-7.
[39]Zaid H, Antonescu CN, Randhawa VK, et al. Insulin action on glucose transporters through molecular switches, tracks and tethers [J]. Biochemical Journal,2008,413:201-15.
[40]Foster LJ, Klip A. Mechanism and regulation of GLUT-4 vesicle fusion in muscle and fat cells [J]. American Journal of Physiology Cell Physiology,2000, 279:C877-C890.
[41]Kawanishi M, Tamori Y, Okazawa H, et al. Role of SNAP23 in insulin-induced translocation of GLUT4 in 3T3-L1 adipocytes. Mediation of complex formation between syntaxin4 and VAMP2 [J]. Journal of Biological Chemistry,2000,275: 8240-7.
[42]McNew JA, Parlati F, Fukuda R, et al. Compartmental specificity of cellular membrane fusion encoded in SNARE proteins [J]. Nature,2000,407:153-9.
[43]Jahn R, Scheller RH. SNAREs-engines for membrane fusion [J]. Nature Molecular Cell Biology,2006,7:631-43.
[44]Latham CF, Lopez JA, Hu SH, et al. Molecular dissection of the Muncl8c/syntaxin4 interaction:implications for regulation of membrane trafficking [J]. Traffic,2006,7:1408-19.
[45]Kanda H, Tamori Y, Shinoda H, et al. Adipocytes from Muncl8c-null mice show increased sensitivity to insulin-stimulated GLUT4 externalization [J]. Journal of Clinical Investigation,2005,115:291-301.
[46]Smithers NP, Hodgkinson CP, Cuttle M, et al. Insulin-triggered repositioning of muncl8c on syntaxin-4 in GLUT4 signalling [J]. Biochemical Journal,2008, 410:255-60.
[47]Olofsson CS, Gopel SO, Barg S, et al. Fast insulin secretion reflects exocytosis of docked granules in mouse pancreatic B-cells [J]. Pflugers Arch,2002, 444(1-2):43-51.
[48]Ivarsson R, Jing X, Waselle L, et al. Myosin 5a controls insulin granule recruitment during late-phase secretion [J]. Traffic,2005,6(11):1027-35.
[49]Chang TJ, Chen WP, Yang C, et al. Serine-385 phosphorylation of inwardly rectifying K+ channel subunit (Kir6.2) by AMP-dependent protein kinase plays a key role in rosiglitazone-induced closure of the K(ATP) channel and insulin secretion in rats [J]. Diabetologia,2009,52(6):1112-21.
[50]Henquin JC. Regulation of insulin secretion:a matter of phase control and amplitude modulation [J]. Diabetologia,2009,52(5):739-51.
[51]. Smith PA, Aschroft FM, Fewtrell CM. Permeation and gating properties of the L-type calcium channel in mouse pancreatic beta cells [J]. J Gen Physiol,1993, 101(5):767-97.
[52]Rorsman P, Renstrom E. Insulin granule dynamics in pancreatic beta cells [J]. Diabetologia,2003,46(8):1029-45.
[53]Anderson M P, Gregory R J, Thompsons, et al. Demonstration that CFTR is a chloride channel bv alteration of its anion selectivity [J]. Science,1991, 253(5016):202-5.
[54]Langosch D, Becker CM, Betz H. The inhibitory glycine receptor:a ligand-gated chloride channel of the central nervous system [J]. Eur J Biochem,1990, 194(1):1-8.
[55]Dutzler R, Campbell EB, Cadene M, et al. X-ray structure of a C1C chloride channel at 3.0 A reveals the molecular basis of anion selectivity [J]. Nature, 2002,415(6869):287-94.
[56].Duan D, Cowley S, Horowitz B, et al. A serineresidue in C1C-3 links phosphorylation-dephosphorylation to chloride channel regulation by cell volume [J]. J Gen Physiol,1999,113:57-70.
[57]Duan D, Winter C, Cowley S, et al. Molecular identification of a volume-regulated chloride channel [J]. Nature,1997,390:417-21.
[58]Li X, Shimada K, Showalter LA et al. Biophysical properties of C1C-3 differentiate it from swelling-activated chloride channels in Chinese hamster ovary-K1 cells [J]. J Biol Chem,2000,275:35994-8.
[59]Stobrawa SM, Breiderhoff T, Takamori S, et al. Disruption of C1C-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus [J]. Neuron,2001,29:185-96.
[60]Al-Awqati Q. Chloride channels of intracellular organelles [J]. Curr Opin Cell Biol,1995,7:504-8.
[61]Szewczyk A. The intracellular potassium and chloride channels:properties, pharmacology and function [J]. Mol Membr Biol,1998,15:49-58.
[62]Woodbury DJ. Evaluation of the evidence for ion channels in synaptic vesicles [J]. Mol Membr Biol,1995,12:165-71.
[63]Maycox PR, Deckwerth T, Hell JW, et al. Glutamate uptake by brain synaptic vesicles. Energy dependence of transport and functional reconstitution in proteoliposomes [J]. J Biol Chem,1988,263:15423-8.
[64]Stobrawa SM, Breiderhoff T, Takamori S, et al. Disruption of C1C-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus [J]. Neuron,2001,29:185-96.
[65]Yamashiro DJ, Maxfield FR.J. Acidification of morphologically distinct endosomes in mutant and wild-type Chinese hamster ovary cells [J]. Cell Biol, 1987,105(6 Pt 1):2723-33.
[66]Moore HP, Andresen JM, Eaton BA, et al. Biosynthesis and secretion of pituitary hormones:dynamics and regulation [J]. Arch Physiol Biochem,2002,110(1-2): 16-25.
[67]Machen TE, Chandy G, Wu M, et al. Cystic fibrosis transmembrane conductance regulator and H+ permeability in regulation of Golgi pH [J]. JOP,2001,2(4 Suppl):229-36.
[68]Nishi T, Forgac M. The vacuolar (H+)-ATPases--nature's most versatile proton pumps [J]. Nat Rev Mol Cell Biol,2002,3(2):94-103.
[69]Grabe M, Oster G.J. Regulation of organelle acidity [J]. Gen Physiol, 2001,117(4):329-44.
[70]Brown D, Paunescu TG, Breton S, et al. Regulation of the V-ATPase in kidney epithelial cells:dual role in acid-base homeostasis and vesicle trafficking [J]. J Exp Biol,2009,212(Pt 11):1762-72.
[71]Devuyst O. Chloride channels and endocytosis:new insights from Dent's disease and CLC-5 knockout mice [J]. Bull Mem Acad R Med Belg,2004,159(Pt 2):212-7.
[72]Hara-Chikuma M, Yang B, Sonawane ND, et al. C1C-3 chloride channels facilitate endosomal acidification and chloride accumulation [J]. J Biol Chem, 2005,280(2):1241-7.
[73]Li DQ, Jing X, Salehi A, et al. Suppression of sulfonylurea- and glucose-induced insulin secretion in vitro and in vivo in mice lacking the chloride transport protein C1C-3 [J]. Cell Metab,2009,10:309-15.
[74]Deriv LV, Gomez EA, Jacobson DA, et al. The granular chloride channel C1C-3 is permissive for insulin secretion [J]. Cell Metab,2009,10:316-23.
[75]Song C, Duan XQ, Zhou Y, et al. Experimental study on islet cells in rats under condition of three-dimensional microgravity [J]. Zhonghua Wai Ke Za Zhi,2004, 42(9):559-61.
[76]Chang XB. Molecular mechanism of ATP-dependent solute transport by multidrug resistance-associated protein 1 [J]. Methods Mol Biol,2010, 596:223-49.
[77]Breedveld P, Benjnen JH, Schellens JHM. Use of P-glycoprotein and BCRP inhibitors to improve oral bioavailability and CNS penetration of anticancer drugs [J]. Trends Pharmacol Sci,2006,27:17—24.
[78]Vanoye CG, Castro AF, Pourcher T, et al Phosphorylation of P-glycoprotein by PKA and PKC modulates swelling-activated Cl- currents [J]. Am J physiol,1999, 276:370-8.
[79]Chinn LW, Kroetz DL. ABCB1 pharmacogenetics:progress, pitfalls, and promise [J]. Clin Pharmacol Ther,2007,81(2):265-9.
[80]Kawai K, Kusano I, IdoM, et al. Identification of a P-Glycoprotein-Related protein (mini-P-glycoprotein) overexpressed in multidrug resistant cells [J]. Biochem Biophys Res Commun,1994,198(2):804-10.
[81]Oselin K, Nowakowski-Gashaw I, Mrozikiewicz PM, et al. Quantitative determination of MDR1 mRNA expression in peripheral blood lymphocytes:a possible role of genetic polymorphisms in the MDR1 gene [J]. Eur J Clin Invest, 2003,33(3):261-7.
[82]Rosengren AH, Jokubka R, Tojjar D, et al. Overexpression of alpha2A-adrenergic receptors contributes to type 2 diabetes [J].Science,2010,327(5962):217-20.
[83]Bartlett MS, Stirling D. A Short History of the Polymerase Chain Reaction [J]. Methods Mol Biol,2003,226:3-6.
[84]Purves. Life:The Science of Biology [M]. USA:Freeman and Company,2001: 214-217.
[85]Michael W. Pfaffl. A new mathematical model for relative quantification in real-time RT-PCR [J]. Nucleic Acids Research,2001,29:9 e45.
[86]Frederique Ponchel, Carmel Toomes, Kieran Bransfield, et al. Real-time PCR based on SYBR-Green I fluorescence:An alternative to the TaqMan assay for a relative quantification of gene rearrangements, gene amplifications and micro gene deletions [J]. BMC Biotechnology,2003,3:18.
[87]H Maeda, C Fujimoto, Y Haruki, et al. Quantitative real-time PCR using TaqMan and SYBR Green for Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, tetQ gene and total bacteria [J]. FEMS Immunol Med Microbiol,2003,39(1):81-6.
[88]Hammond S M, Bernstein E, Beach D, et al. An RNA-directed nuclease mediates posttranscription algene silencing in Drosophila cells [J]. Nature, 2000,404(6775):293-6.
[89]Bernstein E, Caudy A A, Hammond S M, et al. Role for a bidentate ribo nuclease in the initiation step of RNA interference [J]. Nature,2001, 409(6818):363-6.
[90]Yang D, Lu H, Erickson JW. Evidence that processed small dsRNAs may mediate sequence-specific mRNA degradation during RNAi in Drosophlia embryos [J]. CurrBio,2000,1(19):1191-200.
[91]Fire A. RNA triggered gene silencing [J]. TIG,1999,15:358-61.
[92]Kawasaki H, Taira K. Short hairpin type of dsRNAs that are controlled by tRNA(Val) promoter significantly induce RNAi mediated gene silencing in the cytoplasm of human cells [J]. Nucleic Acids Res,2003,31:700-7.
[93]Caplen NJ, Fleenor J, Fire A, et al. dsRNA-mediated gene silencing in cultured Drosophila cells [J]. Gene,2000,252:95-105.
[94]Fire A, Xu S, Montgomery MK, et al. Potent and specific genetic interference by dsRNA in caenorhabditis elegans [J]. Nature,1998,391:806-11.
[95]Zamre PD, Tuschl T, Sharp PA, et al. RNAi dsRNA directs the ATP dependent cleavage of mRNA at 21 to 23 nucleotide intervals [J]. Cell,1999,101:25-33.
[96]朱睿,张开立,邹向阳.RNA干扰(RNAi)技术及其在功能基因组学研究中的应用[J].大连医科大学学报,2003,25(2)：15-7.
[97]Brenner C, Kroener G. Apoptosis:Mitochondria--the death cell integrators [J]. Science,2000,289:1150-1.
[98]Guerrero I, Ruiz i Altaba A. Development. Longing for ligand:hedgehog, patched, and cell death [J]. Science,2003,301 (5634):774-6.
[99]Wajant H. The Fas signaling pathway:more than a paradigm [J]. Science,2002, 296 (5573):1635-6.
[100]Salvesen GS. Caspases and apoptosis [J]. Essays Biochem,2002,38:9-19.
[101]Johnstone RW, Ruefli AA, Smyth MJ. Multiple physiologicl functions for multidrug transporter P-glycoprotein [J]. Trends Biochem Sci,2000,25(1):1-6.
[102]Smyth MJ, Krasovskis E, Sutton VR, et al. The drug efflux protein, P-glycoprotein, additionally protects drug-resistant tumor cells from multiple form of caspase-dependent apoptosis [J]. Proc Nati Acad Sci,1998,95(12): 7024-29.
[103]Gollapudi S, Gupta S. Anti-P-glycoprotein antibody induced apoptosis of activated peripheral blood lymphocytes:a possible role of P-glycoprotein in lymphocyte survival [J]. J Clin Immunol,2001,21(6):420-30.
[104]Cullen KV, Davey RA, Davey MW. Drug resistance does not correlate with resistance to Fas-mediated apoptosis [J]. Leuk Res,2001,25(1):69-75.
[105]Trindade GS, Capella LS, Affonso M, et al. Differences in sensitivity to UVC, UVB and UVC radiation of a multidrug-resistant cell line overexpressing P-glycoprotein [J]. Photochem Photobiol,1999,69(6):694-9.
[106]Ruth AC, Roninson IB. Effects of the multidrug transporter P-glycoprotein on cellular responses to ionizing radiation [J]. Cancer Res,2000,60(10):2576-8
[107]陈俊,张积仁,肖明星,等.P糖蛋白抑制X射线诱导凋亡及对线粒体膜电位的影响[J].中华放射医学与防护杂志,2004,24(4)：297-9.
[108]Ruefli AA, Tainton KM, Darey PK, et al. P-glycoprotein inhibits caspase-8 activation but not formation of the death inducing signal complex (disc) following Fas ligation [J]. Cell Death Differ,2002,9(11):1266-72.
[109]Larsen AK, Escargueil AE, Skladanowski A. Resistance mechanisms associated with altered intracellular distribution of anticancer agents [J]. Pharmacol Ther, 2000,85(3):217-29.
[110]Marquardt D, Center MS. Involvement of vascular H+-adenosine triphoshatase activity in multidrug resesistance HL60 cells [J]. J Natl Cancer Inst,1991, 83(15):1098-102.
[111]Segal MS, Beem E. Effect of pH, ionic charge, and osmolality on cytochrome c-mediated caspase-3 activity [J]. Am J Physiol Cell Physiol,2001,281(4): C1196-204.
[112]Robinson LJ, Roberts WK, LingT T, et al. Human MDR1 protein overexpression delays the apoptotic cascade in Chinese hamster ovary fibroblast [J]. Biochemistry,1997,36(37):11169-78.
[113]Idriss HT, Hunnun YA, Boulpaep E, et al. Regulation of volume-activated channels by P-glycoprotein:phosphorylatin has the final say [J]. J Physiol,2000, 524(3):629-36.
[114]Bezombes C, Maestre N, Laurent G, et al. Restoration of TNF-alpha-induced ceramide generation and apoptosis in resistant human leukemia KG1a cells by the P-glycoprotein blocker PSC833 [J]. FASEB J,1998,12(1):101-9.
[115]Lucci A, ChoWI, Han TY, et al. Glucosylceramide:a marker for multiple-drug resistant cancers [J]. Anticancer Res,1998,18(1B):475-80.
[116]Lavie Y, Cao HT, Volner A, et al. Agents that reverse multidrug resistance, tamoxifen, verapamil, and cyclosporin A, block glycosphingolipid metabolism by inhibiting ceramide glycosylation in human cancer cells [J]. J Biol Chem, 1997,272(3):1682-7.
[117]Sathiyapriya V, Bobby Z, Agrawal A, et al. Protein glycation, insulin sensitivity and pancreatic beta cell function in high-risk, non-diabetic, first degree relatives of patients with type 2 diabetes [J]. Indian J Physiol Pharmacol,2009, 53(2):163-8.
[118]Mulder H, Ling C. Mitochondrial dysfunction in pancreatic beta-cells in Type 2 diabetes [J]. Mol Cell Endocrinol,2009,297(1-2):34-40.
[119]Wajchenberg BL.Beta-cell failure in diabetes and preservation by clinical treatment [J]. Endocr Rev,2007,28(2):187-218.
[120]Wan J, Jiang L, Lu Q, et al. Activation of PPARdelta up-regulates fatty acid oxidation and energy uncoupling genes of mitochondria and reduces palmitate-induced apoptosis in pancreatic beta-cells [J]. Biochem Biophys Res Commun,2010,391(3):1567-72.
[121]Del Prato S. Role of glucotoxicity and lipotoxicity in the pathophysiology of Type 2 diabetes mellitus and emerging treatment strategies [J]. Diabet Med, 2009,26(12):1185-92.
[122]Clark A, Wells CA, Buley ID, et al. Islet amyloid, increased A-cells, reduced B-cell and exocrine fibrosis:quantitative changes in the pancreas in type 2 diabetes [J]. Diabetes Res,1988,9(4):151-9.
[123]Janson J, Ashley RH, Harrison D, et al. The mechanism of islet amyloid polypeptide toxicity is membrane disruption by intermediate-sized toxic amyloid particles [J]. Diabetes,1999,48:491-8.
[124]Janciauskiene S, Ahren B. Fibrillar islet amyloid polypeptide differentially affects oxidative mechanisms and lipoprotein uptake in correlation with cytotoxicity in two insulin-producing cell lines [J]. Biochem Biophys Res Commun,2000,267:619-25.
[125]Ajabnoor MA, EI-Naggar MM, Elayat AA, et al.. Functional and morphological study of cultured pancreatic islets treated with cyclosporine [J]. Life Sci,2007, 80:345-55.
[126]Gottesman M M, Fojo T, Bates S E. Multidrug resistance in cancer:role of ATP-dependent transporters [J]. Nat Rev Cancer,2002,2:48-58.
[127]Gottesman M M, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter [J]. Ann Rev Biochem,1993,62:385-427.
[128]Witherspoon S M, Emerson D L, Kerr B M, et al. Flow cytometric assay of modulation of P-glycoprotein function in whole blood by the multidrug resistance inhibitor GG918 [J]. Clin Cancer Res,1996,2:7-12.
[129]Ferry D R, Traunecker H, Kerr D J. Clinical trials of P-glycoprotein reversal in solid tumours [J]. Eur J Cancer,1996,32A:1070-1081.
[130]Baumert C, Hilgeroth A. Recent advances in the development of P-gp inhibitors[J]. Anticancer Agents Med Chem,2009,9(4):415-36.
[131]Hjelmasaeth J, Hagen LT, Asberg A, et al. The impact of short-term cyclosporin A treatment on insulin secretion and insulin sensitivity in man [J]. Nephrol Dial Transplant,2007,22(6):1743-9.
[132]Montori VM, Basu A, Erwin PJ, et al. Posttransplantation diabetes:a systematic review of the literature[J]. Diabetes Care,2002,25:583-92.
[133]van Duijnhoven EM, Boots JMM, Christiaans MHL, et al. Influence of tacrolimus on glucose metabolism before and after renal transplantation:a prospective study[J]. J Am Soc Nephrol,2001,12:583-8.
[134]Robertson RP, Franklin G, Nelson L. Intravenous glucose tolerance and pancreatic islet beta-cell function in patients with multiple sclerosis during 2-yr treatment with cyclosporin[J]. Diabetes,1989,38:58-64.
[135]Nam JH, Mun JI, Kim SI, et al. Beta-Cell dysfunction rather than insulin resistance is the main contributing factor for the development of postrenal transplantation diabetes mellitus[J]. Transplantation,2001,71:1417-23.
[136]SatoT, Inagaki A, Uchida K, et al. Diabetes mellitus after transplant:relationship to pretransplant glucose metabolism and tacrolimus or cyclosporine A-based therapy[J]. Transplantation,2003,76:1320-6.
[137]Caumo A and Luzi L. First-phase insulin secretion:does it exist in real life? Considerations on shape and function [J]. Am J Physiol Endocrinol Metab,2004, 287:E371-8.
[138]Doyle ME, Egan JM. Pharmacological agents that directly modulate insulin secretion [J]. Pharmacol Rev,2003,55:105-131.
[139]Oetjen E, Thoms KM, Laufer Y, et al. The immunosuppressive drugs cyclosporin A and tacrolimus inhibit membrane depolarization-induced CREB transcriptional activity at the coactivator level [J]. Br J Pharmacol,2005, 144:982-93.
[140]Schwaninger M, Blume R, Oetjen E, et al. Inhibition of cAMP-responsive element-mediated gene transcription by cyclosporin A and FK506 after membrane depolarization [J]. J Biol Chem,1993,268:23111-5.
[141]Lawrence MC, Bhatt HS, Watterson JM, et al. Regulation of insulin gene transcription by a Ca(2+)-responsive pathway involving calcineurin and nuclear factor of activated T cells [J]. Mol Endocrinol 2001,15:1758-67.
[142]Lawrence MC, Bhatt HS, Easom RA. NFAT regulates insulin gene promoter activity in response to synergistic pathways induced by glucose and glucagon-like peptide-1 [J]. Diabetes,2002,51:691-8.
[143]Konrad T, Steinmuller T, Vicini P, et al. Regulation of glucose tolerance in patients after liver transplantation:impact of cyclosporin versus tacrolimus therapy [J]. Transplantation,2000,69:2072-8.
[144]Dresner LS, Andersen DK, Kahng KU, et al. Effects of cyclosporine on glucose metabolism [J]. Surgery,1989,106:163-9.
[145]Bratanova-Tochkova TK, Cheng H, Daniel S, et al. Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion [J]. Diabetes,2002, 51(Suppl_1):S83-S90.
[146]Donelan MJ, Morfini G, Julyan R, et al. Ca2+-dependent dephosphorylation of kinesin heavy chain on beta-granules in pancreatic beta-cells. Implications for regulated beta-granule transport and insulin exocytosis [J]. J Biol Chem,2002, 277:24232-42.
[147]Drachenberg CB, Klassen DK, Weir MR, et al. Islet cell damage associated with tacrolimus and cyclosporine:morphological features in pancreas allograft biopsies and clinical correlation [J]. Transplantation,1999,68:396-402.
[148]Nielsen JH, Mandrup-Poulsen T, Nerup J. Direct effects of cyclosporin A on human pancreatic beta-cells [J]. Diabetes,1986,35:1049-52.
[149]Fuhrer DK, Kobayashi M, Jiang H. Insulin release and suppression by tacrolimus, rapamycin and cyclosporin A are through regulation of the ATP-sensitive potassium channel [J]. Diabetes Obes Metab,2001,3:393-402.
[150]Ebihara K, Fukunaga K, Matsumoto K, et al. Cyclosporin A stimulation of glucose-induced insulin secretion in MIN6 cells [J]. Endocrinology,1996,137: 5255-63.
[1]韩贻仁.分子细胞生物学[M].北京：科学出版社,2001：126.
[2]孙大业,马力耕,崔素娟.细胞信号转导[M].北京：科学出版社,2001：228.
[3]李俊敏,刘朝晖,尚忠林.细胞膜上的离子通道[J].河北师范大学学报(自然科学版),2005,29：519-22.
[4]张宗明,裘法祖.离子通道与疾病[J].World Chin J Digestol,2005,13(5)：585-7.
[5]Hatta S, Sakamoto T, Horio Y. Ion channels and diseases[J]. Med Electron M icrosc,2002,35:117-26.
[6]张晓东,臧益民,周士胜等.CIC通道的生物学及相关疾病[J].生理科学进展,2001,32(4)：327-30.
[7]Jentsch TJ, Friedrich T, Schrier A, et al. The C1C chloride channel family [J]. Eur J Physiol,1999,437:783-95.
[8]张晓东,臧益民,周士胜.心脏氯离子通道研究进展[J].心脏杂志,2000,12：473-7.
[9]Fahlke C, Rhodes TH, Desai RR, et al. Pore sloiehiomet of a voltage-gated chloride chmnnel [J]. Nature,1998,394:687-90.
[10]Saviance C, Conli F, Pusch M. The muscle chloride channel C1C-1 has double barreled appearance that is differently affected in dominant and recessive myotonia [J]. J Fen Physio 1,1999,113:457-67.
[11]Jentsch TJ, Steinmeyer K, Schwarz G. Primary structure of Torpedo mamorata chloride channel isolated by expression cloning in Xenopus oocytes [J]. Nature, 1990,348:510-4.
[12]Kawasaki M, Uchida S, Monkawa T, et al. Cloning and expression of a protein C-regulated chloride channel abundantly expressed in rat brain neuronal ceils [J]. Neuron,1994,12:597-604.
[13]Borsani G, Rugarli El, Taglialatela M, et al. Characterization of a human and murine gene (CLCN3) sharing similarities to voltage-gated chloride channels and to a yeast integral membrane protein [J]. Genomics,1995,27:131-41.
[14]Vogalis F, Vincent T, Oureshi I, et al. Cloning and expression of the large-conductance Ca2+-activated K+ channel from colonic smooth muscle [J]. Am J Physiol,1996,271:G629-39.
[15]Britton FC, Hatton WJ, Rossow CF, et al. Molecular distribution of volume-regulated chloride channels (C1C-2 and CIC—3) in cardiac tissues [J]. Am J Physiol Heart Circ Physiol,2000,279(5):H2225-33.
[16]Shimada K, Li X, Xu G, et al. Expresion and canalicular localization of two isoforms of the CIC-3 chloride channel from rat hepatocytes [J]. Am J Physiol Gastrointest Liver Physiol,2000,279(2):G268～76.
[17]Huang P, Liu J, Di A, et al. Regulation of human CIC-3 channels by multifunctional Ca2+ /calmodulin dependent protein kinase [J]. J Biol Chem, 2001,276(23):20093-100.
[18]Duan D, W inter C, Cowley S, et al. Molecular identification of a volume regulated chloride channel [J]. Nature,1997,390(6658):417-21.
[19]Duan D, Cowley S, Horowitz B, et al. A serine residue in CIC-3 links phosphorylation-dephosphorylation to chloride channel regulation by cell volume [J]. J Gen Physiol,1999,113(1):57-70.
[20]Li X, Shimada K, Showalter LA, et al. Biophysical properties of CIC-3 differentiate it from swelling-activated chloride channels in Chinese hamster ovary-KI cells [J]. J Biol Chem,2000,275(46):35994-8.
[21]Dick GM, Bradley KK, Horowitz B, et al. Functional and molecular identification of a novel chloride conductance in canine colonic smoth muscle [J]. Am J Physiol,1998,275(4 Pt 1):C940-50.
[22]von Weikersthal SF, Barrand MA, Hladky SB. Functional and molecular characterization of a volume-sensitive chloride current in rat brain endothelial cells [J]. J Physiol,1999,516(Pt 1):75-84.
[23]Wang L, ChenL, JacobTJ. The role of CIC-3 in volume-activated chloride currents and volume regulation in bovine epithelial cells demonstrated by antisense inhibition [J]. J Physiol,2000,524(Pt1):63-75.
[24]Duan D, Zhong J, Hermoso M, et al. Functional inhibition of native volume-sensitive outwardly rectifying anion chanels in muscle cells and Xenopus oocytes by anti-C1C-3 antibody [J]. J Physiol,2001,531(Pt 2): 437-44.
[25]Tseng GN. Cell sweling increases membrane conductance of canine cardiac cells:Evidence for a volume-sensitive Cl channel [J]. Am J Physiol,1992,262(4 Pt 1):C1056-68.
[26]Sorota S. Swelling-induced chloride-sensitive current in canine a trial cells revealed by whole-cell patch-clamp method [J]. Circ Res,1992,70(4):679-87.
[27]Kawasaki M, Suzuki M, Uchida S, et al. Stable and functional expression of the C1C-3 chloride channel in somatic cell lines [J]. Neuron,1995,14(6):1285-91.
[28]Keenan C, Kelleher D. Protein kinase C and the cytoskeleton [J]. Cell Signal, 1998,10(4):225-32.
[29]Hume JR, Duan D, Collier ML, et al. Anion transport in heart [J]. Physiol Rev, 2000,80(1):31-81.
[30]Obermuller N, Gretz N, Kriz W, et al. The swelling-activated chloride channel CIC-2, the chloride channel CIC-3. and CIC-5, a chloride channel mutated in kidney stone disease, are expressed in distinct subpopulations of renal epithelial cells [J]. J Clin Invest,1998,101(3):635-42.
[31]Stobrawa SM, Breiderhoff T, Takamori S, et al. Disruption of CIC-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus [J]. Neuron,2001,29(1):185-96.
[32]Kinard TA, Goforth PB, Tao Q, et al. Chloride channels regulate HIT cell volume but cannot fully account for swelling-induced insulin secretion [J]. Diabetes,2001,50(5):992-1003.
[33]Weylandt KH, Valverde MA, Nobles M, et al. Human CIC-3 is not the swelling-activated chloride channel involved in cell volume regulation [J]. J Biol Chem,2001,276(20):17461-7.
[34]Du XY, Sorota S. Protein kinase C stimulates swelling-induced chloride current in canine atrial cells [J]. Pflugers Arch,1999,437(2):227-34.
[35]Waldegger S, Barth P, Raber G, et al. Cloning and characterization of a putative human serine/threonine protein kinase transcriptionally modified during anisotonic and isotonic alterations of cell volume [J]. Proc Nalt Acad Sci,1997, 94:4440-5.
[36]Frank Thevenod. Ion channels in secretary granules of the pancreas and their role in exocytosis and release of secretory proteins [J]. Am J Physiol Cell Physiol, 2002,283:C651-C672.
[37]Bokvist K, Holmqvist M, Gromada J, et al. Compound exocytosis in voltage-clamped mouse pancreatic beta-cells revealed by carbon fibre amperometry [J]. Pflu" gers Arch,2000,439:634-45.
[38]Bosl MR, Stein V, Hubner C, et al. Male germ cells and photoreceptors, both dependent on close cell-cell interactions, degenerate upon C1C-2 Cl- channel disruption [J]. EMBO J,2001,20:1289-99.
[39]Duan D, Cowley S, Horowitz B, et al. A serineresidue in C1C-3 links phosphorylation-dephosphorylation to chloride channel regulation by cell volume [J]. J Gen Physiol,1999,113:57-70.
[40]Duan D, Winter C, Cowley S, et al. Molecular identification of a volume-regulated chloride channel [J]. Nature,1997,390:417-21.
[41]Li X, Shimada K, Showalter LA, et al. Biophysical properties of C1C-3 differentiate it from swelling-activated chloride channels in Chinese hamster ovary-Kl cells [J]. J Biol Chem,2000,275:35994-8.
[42]Stobrawa SM, Breiderhoff T, Takamori S, et al. Disruption of C1C-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus [J]. Neuron,2001,29:185-96.
[43]Al-Awqati Q. Chloride channels of intracellular organelles [J]. Curr Opin Cell Biol,1995,7:504-8.
[44]Szewczyk A. The intracellular potassium and chloride channels:properties, pharmacology and function [J]. Mol Membr Biol,1998,15:49-58.
[45]Woodbury DJ. Evaluation of the evidence for ion channels in synaptic vesicles [J]. Mol Membr Biol,1995,12:165-71.
[46]Maycox PR, Deckwerth T, Hell JW, et al. Glutamate uptake by brain synaptic vesicles. Energy dependence of transport and functional reconstitution in proteoliposomes [J]. J Biol Chem,1988,263:15423-8.
[47]Stobrawa SM, Breiderhoff T, Takamori S, et al. Disruption of C1C-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus [J]. Neuron,2001,29:185-96.
[48]Barg S, Huang P, Eliasson L, et al. Priming of insulin granules for exocytosis by granular Cl- uptake and acidification [J]. J Cell Sci,2001,114:2145-54.
[49]Corkey BE, Deeney JT, Yaney GC, et al. The role of long-chain fatty acyl-CoA esters in beta-cell signal transduction [J]. J Nutr,2000,130:299S-304S.
[50]Deeney JT, Prentki M, Corkey BE. Metabolic control of beta-cell function [J]. Semin Cell Dev Biol,2000,11:267-75.
[51]Ashcroft FM, Rorsman P. Electrophysiology of the pancreatic beta-cell [J]. Prog Biophys Mol Biol,1989,54:87-143.
[52]Lang J. Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrine secretion [J]. Eur J Biochem,1999,259:3-17.
[53]Hutton JC. Insulin secretory granule biogenesis and the proinsulin-processing endopeptidases [J]. Diabetologia,1994,37:S48-S56.
[54]Jahn R, Su" dhof TC. Membrane fusion and exocytosis [J]. Annu Rev Biochem, 1999,68:863-911.
[55]Eliasson L, Renstrom E, Ding WG, et al. Rapid ATP-dependent priming of secretory granules precedes Ca2+-induced exocytosis in mouse pancreatic B-cells [J]. J Physiol,1997,503:399-412.
[56]Renstrom E, Eliasson L, Bokvist K, et al.Cooling inhibits exocytosis in single mouse pancreatic B-cells by suppression of granule mobilization [J]. J Physiol, 1996,494:41-52.
[57]Hou JC, Min L, Pessin JE. Insulin granule biogenesis, trafficking and exocytosis [J]. Vitam Horm,2009,80:473-506.
[58]Del Prato S, Marchetti P, Bonadonna RC. Phasic insulin release and metabolic regulation in type 2 diabetes [J]. Diabetes,2002,51:S109-116.
[59]Rorsman P, Eliasson L, Renstrom E, et al. The cell physiology of biphasic insulin secretion [J]. News Physiol Sci,2000,15:72-7.
[60]Porte D Jr. Banting lecture 1990. Beta-cells in type Ⅱ diabetes mellitus [J]. Diabetes,1991,40:166-80.
[61]Henquin JC. The fiftieth anniversary of hypoglycaemic sulphonamides. How did the mother compound work [J]? Diabetologia,1992,35:907-12.
[62]Ashcroft SJ, Niki I, Kenna S, et al. The beta-cell sulfonylurea receptor [J]. Adv Exp Med Biol,1993,334:47-61.
[63]Trube G, Rorsman P, Ohno-Shosaku T. Opposite effects of tolbutamide and diazoxide on the ATP-dependent K+channel in mouse pancreatic beta-cells [J]. Pflu" gers Arch,1986,407:493-9.
[64]Aguilar-Bryan L, Nichols CG, Wechsler S, et al. Cloning of the beta-cell high-affinity sulfonylurea receptor:a regulator of insulin secretion [J]. Science, 1995,268:423-6.
[65]De Lisle RC, Schulz I, Tyrakowski, et al. Isolation of stable pancreatic zymogen granules [J]. Am J Physiol Gastrointest Liver Physiol,1984,246:G411-8.
[66]Litman T, Druley TE, Stein WD, et al. From MDR to MXR:new understanding of multidrug resistance systems, their properties and clinical significance [J]. Cell Mol Life Sci,2001,58:931-59.
[67]Inagaki N, Gonoi T, Clement JP, et al. Reconstitution of KATP:an inward rectifier subunit plus the sulfonylurea receptor [J]. Science,1995,270:1166-70.
[68]Carpentier JL, Sawano F, Ravazzola M, et al. Internalization of 3H-glibenclamide in pancreatic islet cells [J]. Diabetologia,1986,29:259-61.
[69]Ozanne SE, Guest PC, Hutton J, et al. Intracellular localization and molecular heterogeneity of the sulphonylurea receptor in insulin-secreting cells [J]. Diabetologia,1995,38:277-82.
[70]Palade G, Szewczyk A. Intracellular targets for antidiabetic sulfonylureas and potassium channel openers [J]. Biochem Pharmacol,1997,54:961-5.
[71]Eliasson L, Renstrom E, Ammala C, et al. PKC-dependent stimulation of exocytosis by sulfonylureas in pancreatic beta-cells [J]. Science,1996,271: 813-5.
[72]The'venod F, Anderie I, Schulz I. Monoclonal antibodies against MDR1 P-glycoprotein inhibit chloride conductance and label a 65-kDa protein in pancreatic zymogen granule membranes [J]. J Biol Chem,1994,269:24410-7.
[73]The'venod F, Chathadi KV, Jiang B, et al. ATPsensitive K+conductance in pancreatic zymogen granules:block by glyburide and activation by diazoxide [J]. J Membr Biol,1992,129:253-66.
[74]The'venod F, Hildebrandt JP, Striessnig J, et al. Chloride and potassium conductances of mouse pancreatic zymogen granules are inversely regulated by a approximately 80-kDa mdrla gene product [J]. J Biol Chem,1996, 271:3300-5.
[75]Barg S, Renstro"m E, Berggren PO, et al. The stimulatory action of tolbutamide on Ca2+-dependent exocytosis in pancreatic cells is mediated by a 65 kDa mdr-like P-glycoprotein [J]. Proc Natl Acad Sci,1999,96:5539-44.
[76]Shindo T, Yamada M, Isomoto S, et al. SUR2 subtype (A and B)-dependent differential activation of the cloned ATP-sensitive K+ channels by pinacidil and nicorandil [J]. Br J Pharmacol,1998,124:985-91.
[77]Dunne MJ, Petersen OH. Intracellular ADP activates K+channels that are inhibited by ATP in an insulin-secreting cell line [J]. FEBS Lett,1986,208: 59-62.
[78]Kakei M, Kelly RP, Ashcroft SJ, et al. The ATP-sensitivity of K+channels in rat pancreatic B-cells is modulated by ADP [J]. FEBS Lett,1986,208:63-6.
[79]Misler S, Falke LC, Gillis K, et al. A metabolite-regulated potassium channel in rat pancreatic B cells [J]. Proc Natl Acad Sci,1986,83:7119-23.
[80]Braun M, Anderie I, The'venod F. Evidence for a 65 kDa sulfonylurea receptor in rat pancreatic zymogen granule membranes [J]. FEBS Lett,1997,411:255-9.
[81]The'venod F, Chathadi KV, Jiang B, et al. ATPsensitive K+conductance in pancreatic zymogen granules:block by glyburide and activation by diazoxide [J]. J Membr Biol,1992,129:253-66.
[82]Kirk J, Syed SK, Harris AL, et al. Reversal of P-glycoproteinmediated multidrug resistance by pure anti-oestrogens and novel tamoxifen derivatives [J]. Biochem Pharmacol,1994,48:277-85.
[83]Sutton RB, Fasshauer D, Jahn R, et al. Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 (?) resolution [J]. Nature,1998,395: 347-53.
[84]Ungermann C, Wickner W, Xu Z. Vacuole acidification is required for trans-SNARE pairing, LMA1 release, and homotypic fusion [J]. Proc Natl Acad Sci,1999,96:11194-9.
[85]De Lisle RC, Williams JA. Zymogen granule acidity is not required for stimulated pancreatic protein secretion [J]. Am JPhysiol Gastrointest Liver Physiol,1987,253:G711-9.
[86]Curry DL, Bennett LL, Grodsky GM:Dynamics of insulin secretion by the perfused rat pancreas [J]. Endocrinology,1968,83(3):572-84.
[87]Henquin JC, Nenquin M, Stiernet P, et al. In Vivo and In Vitro Glucose-Induced Biphasic Insulin Secretion in the Mouse:Pattern and Role of Cytoplasmic Ca2+ and Amplification Signals in {beta}-Cells [J]. Diabetes,2006,55(2):441-51.
[88]Fehse F, Trautmann M, Holst JJ, et al. Exenatide augments firstand second-phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes [J]. J Clin Endocrinol Metab,2005,90(11):5991-7.
[89]Jiaqiang Ren, Ping Jin, Ena Wang, et al. Pancreatic islet cell therapy for type I diabetes:understanding the effects of glucose stimulation on islets in order to produce better islets for transplantation [J]. Journal of Translational Medicine, 2007,5:1-15.
[90]Kwan EP, Gaisano HY. Glucagon-like peptide 1 regulates sequential and compound exocytosis in pancreatic islet betacells [J]. Diabetes,2005,54(9): 2734-43.
[91]Bratanova-Tochkova TK, Cheng H, Daniel S, et al. Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion [J]. Diabetes,2002, 51(Suppl 1):S83-90.
[92]Rorsman P, Renstrom E:Insulin granule dynamics in pancreatic beta cells [J]. Diabetologia,2003,46(8):1029-45.
[93]Daniel S, Noda M, Straub SG, et al. Identification of the docked granule pool responsible for the first phase of glucose-stimulated insulin secretion [J]. Diabetes,1999,48(9):1686-90.
[94]兰李,周云燕,杨志勇等.活细胞钙离子浓度荧光显微检测系统的研制和应用[J].生物医学工程研究,2004,23：114-7.
[95]Chorbachi R, Graham JM, Ford J, et al. Cochlear implantation in Jervell and Lange—Nielsen syndrome [J]. Int J Pediatr Otorhinolaryngol,2002,66:213— 21.
[96]Hosaka Y, Hanawa H, Washizuka T, et al. Function subcellular localization and assembly of a novel mutation of KCNJ2 in Andersen s syndrome [J]. J Mol Cell Cardiol,2003,35:409-15.
[97]Swift PA, MacGregor GA. The epithelial sodium channel in hypertension: genetic heterogeneity and implications for treatment with amiloride [J]. Am J Pharmacogenomics,2004,4:161-8.
[98]Spampanato J, Keamey JA, de Haan G, et al. A novel epilepsy mutation in the sodium channel SCN 1A identifies a cytoplasmic domain for beta subunit interaction [J]. J Neurosci,2004,24:10022-34.
[99]Nishimune H, Sanes IR, Carlson SS. A synaptic laminin-calcium channel interaction organizes active zones in motor new eterminals [J]. Nature,2004, 432:580-7.
[100]Waldegger S, lentsch. Functional and structural analysis of C1C-K chloride channels involved in renal disease [J]. J Biol Chem,2000,275:24527—33.
[2]Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones:a meta-analysis of randomized clinical trials [J]. Lancet,2007,370:1129-36.
[3]Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes [J]. N Engl J Med,2007, 356:2457-71.
[4]Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD):a multicentre, randomised, open-label trial [J]. Lancet,2009, 373:2125-35.
[5]Diamond GA, Bax L, Kaul S. Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death [J]. Ann Intern Med, 2007,147:578-81.
[6]Lincoff AM, Wolski K, Nicholls SJ, et al. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus:a meta-analysis of randomized trials [J]. JAMA,2007,298:1180-8.
[7]Lipscombe LL, Gomes T, Levesque LE, et al. Thiazolidinediones and cardiovascular outcomes in older patients with diabetes [J]. JAMA,2007, 298:2634-43.
[8]Evans J, Ogston S, Emslie-Smith A, Morris A. Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes:a comparison of patients treatedwith sulphonylureas andmetformin. Diabetologia 2006; 49:930-6.
[9]Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes [J]. N Engl J Med,2008, 358:2545-59.
[10]ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes [J]. N Engl J Med,2008,358:2560-72.
[11]中华医学会糖尿病学分会.《中国2型糖尿病防治指南》(试行本)(节选)[J].中国慢性病预防与控制,2004,126：283-5.
[12]Yi Lin, Zhongjie Sun. Current views on type 2 diabetes [J]. Journal of Endocrinology,2010,204:1-11.
[13]Das SK, Elbein SC. The genetic basis of type 2 diabetes [J]. Cell science,2006, 2:100-31.
[14]Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes:principles of pathogenesis and therapy [J]. Lancet,2005,365:1333-46.
[15]DeFronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of NIDDM. A balanced overview [J]. Diabetes Care,1992,15:318-68.
[16]Hou JC, Min L, Pessin JE. Insulin granule biogenesis, trafficking and exocytosis [J]. Vitam Horm,2009,80:473-506.
[17]Del Prato S, Marchetti P, Bonadonna RC. Phasic insulin release and metabolic regulation in type 2 diabetes [J]. Diabetes,2002,51:S109-16.
[18]Barg S, Lindqvist A, Obermuller S. Granule docking and cargo release in pancreatic beta-cells [J]. Biochem Soc Trans,2008,36(pt 3):294-9.
[19]Barg S, Huang P, Eliasson L, et al. Priming of insulin granules for exocytosis by granular Cl(-) uptake and acidification [J]. J Cell Sci,2001,114:2145-54.
[20]Michael A. Burke, R. Kannan Mutharasan, et al. The Sulfonylurea Receptor, an Atypical ATP-Binding Cassette Protein, and Its Regulation of the KATP Channel [J]. Circ Res,2008,102:164-76.
[21]Rees DC, Johnson E, Lewinson O. ABC transporters:the power to change [J]. Nature Reviews Molecular Cell Biology,2009,10:218-27.
[22]Sebastian Barg, Erik Renstrom, Per-Olof Berggren, et al. The stimulatory action of tolbutamide on Ca2+-dependent exocytosis in pancreatic b cells is mediated by a 65-kDa mdr-like P-glycoprotein [J]. Proc. Natl. Acad. Sci,1999,96:5539-44.
[23]Thevenod F. Ion channels in secretory granules of the pancreas and their role in exocytosis and release of secretory proteins [J]. Am J Physiol Cell Physiol,2002, 283:C651-672.
[24]Gotoh M, Maki T, Kiyoizumi T, et al. An improved method for isolation of mouse panreatic islets [J]. Transplantation,1985,40:437-8.
[25]Straub SG, Sharp GW. Glucose-stimulated signaling pathways in biphasic insulin secretion [J]. Diabetes Metab Res Rev,2002,18(6):451-63.
[26]Del Prato S. Loss of early insulin secretion leads to postprandial hyperglycaemia [J]. Diabetologia,2003,46 Suppl 1:M2-8.
[27]Rorsman P, Eliasson L, Renstrom E, et al. The Cell Physiology of Biphasic Insulin Secretion [J]. News Physiol Sci,2000,15:72-7.
[28]Straub S, Shanmugam G, Sharp G.. Stimulation of insulin release by glucose is associated with an increase in the number of docked granules in the β-cells of rat pancreatic islets [J]. Diabetes,2004,53:3179-83.
[29]Ohara-Imaizumi M. Imaging analysis reveals mechanistic differences between first- and second-phase insulin exocytosis [J]. J Cell Biol,2007,177:695-705.
[30]Merrins MJ, Stuenkel EL. Kinetics of Rab27a-dependent actions on vesicle docking and priming in pancreatic beta-cells [J].J Physiol.,2008,586(Pt 22):5367-81.
[31]Vikman J, Ma X, Hockerman GH, et al. Antibody inhibition of synaptosomal protein of 25 kDa (SNAP-25) and syntaxin 1 reduces rapid exocytosis in insulin-secreting cells [J]. J Mol Endocrinol,2006,36(3):503-15.
[32]Barg S, Eliasson L, Renstrom E, et al. A subset of 50 secretory granules in close contact with L-type Ca2+ channels accounts for first-phase insulin secretion in mouse beta-cells [J].Diabetes,2002,51 Suppl 1:S74-82.
[33]Renstrom E, Eliasson L, Bokvist K, et al. Cooling inhibits exocytosis in single mouse pancreatic B-cells by suppression of granule mobilization [J]. J Physiol, 1996,494 (Pt 1):41-52.
[34]Sweet IR, Gilbert M. Contribution of calcium influx in mediating glucose-stimulated oxygen consumption in pancreatic islets [J]. Diabetes,2006, 55(12):3509-19.
[35]Wang Z, Thurmond DC. Mechanisms of biphasic insulin-granule exocytosis-roles of the cytoskeleton, small GTPases and SNARE proteins [J]. J Cell Sci, 2009,122(Pt 7):893-903.
[36]Oh E, Thurmond DC. Muncl8c depletion selectively impairs the sustained phase of insulin release [J].Diabetes,2009,58(5):1165-74.
[37]Joost HG, Bell GI, Best JD, et al. Nomenclature of the GLUT/SLC2A family of sugar/polyol transport facilitators [J]. American Journal of Physiology Endocrinology and Metabolism,2002,282:E974-E976.
[38]BjornholmM, Zierath JR. Insulin signal transduction in human skeletal muscle: identifying the defects in type Ⅱ diabetes [J]. Biochemical Society Transactions, 2005,33:354-7.
[39]Zaid H, Antonescu CN, Randhawa VK, et al. Insulin action on glucose transporters through molecular switches, tracks and tethers [J]. Biochemical Journal,2008,413:201-15.
[40]Foster LJ, Klip A. Mechanism and regulation of GLUT-4 vesicle fusion in muscle and fat cells [J]. American Journal of Physiology Cell Physiology,2000, 279:C877-C890.
[41]Kawanishi M, Tamori Y, Okazawa H, et al. Role of SNAP23 in insulin-induced translocation of GLUT4 in 3T3-L1 adipocytes. Mediation of complex formation between syntaxin4 and VAMP2 [J]. Journal of Biological Chemistry,2000,275: 8240-7.
[42]McNew JA, Parlati F, Fukuda R, et al. Compartmental specificity of cellular membrane fusion encoded in SNARE proteins [J]. Nature,2000,407:153-9.
[43]Jahn R, Scheller RH. SNAREs-engines for membrane fusion [J]. Nature Molecular Cell Biology,2006,7:631-43.
[44]Latham CF, Lopez JA, Hu SH, et al. Molecular dissection of the Muncl8c/syntaxin4 interaction:implications for regulation of membrane trafficking [J]. Traffic,2006,7:1408-19.
[45]Kanda H, Tamori Y, Shinoda H, et al. Adipocytes from Muncl8c-null mice show increased sensitivity to insulin-stimulated GLUT4 externalization [J]. Journal of Clinical Investigation,2005,115:291-301.
[46]Smithers NP, Hodgkinson CP, Cuttle M, et al. Insulin-triggered repositioning of muncl8c on syntaxin-4 in GLUT4 signalling [J]. Biochemical Journal,2008, 410:255-60.
[47]Olofsson CS, Gopel SO, Barg S, et al. Fast insulin secretion reflects exocytosis of docked granules in mouse pancreatic B-cells [J]. Pflugers Arch,2002, 444(1-2):43-51.
[48]Ivarsson R, Jing X, Waselle L, et al. Myosin 5a controls insulin granule recruitment during late-phase secretion [J]. Traffic,2005,6(11):1027-35.
[49]Chang TJ, Chen WP, Yang C, et al. Serine-385 phosphorylation of inwardly rectifying K+ channel subunit (Kir6.2) by AMP-dependent protein kinase plays a key role in rosiglitazone-induced closure of the K(ATP) channel and insulin secretion in rats [J]. Diabetologia,2009,52(6):1112-21.
[50]Henquin JC. Regulation of insulin secretion:a matter of phase control and amplitude modulation [J]. Diabetologia,2009,52(5):739-51.
[51]. Smith PA, Aschroft FM, Fewtrell CM. Permeation and gating properties of the L-type calcium channel in mouse pancreatic beta cells [J]. J Gen Physiol,1993, 101(5):767-97.
[52]Rorsman P, Renstrom E. Insulin granule dynamics in pancreatic beta cells [J]. Diabetologia,2003,46(8):1029-45.
[53]Anderson M P, Gregory R J, Thompsons, et al. Demonstration that CFTR is a chloride channel bv alteration of its anion selectivity [J]. Science,1991, 253(5016):202-5.
[54]Langosch D, Becker CM, Betz H. The inhibitory glycine receptor:a ligand-gated chloride channel of the central nervous system [J]. Eur J Biochem,1990, 194(1):1-8.
[55]Dutzler R, Campbell EB, Cadene M, et al. X-ray structure of a C1C chloride channel at 3.0 A reveals the molecular basis of anion selectivity [J]. Nature, 2002,415(6869):287-94.
[56].Duan D, Cowley S, Horowitz B, et al. A serineresidue in C1C-3 links phosphorylation-dephosphorylation to chloride channel regulation by cell volume [J]. J Gen Physiol,1999,113:57-70.
[57]Duan D, Winter C, Cowley S, et al. Molecular identification of a volume-regulated chloride channel [J]. Nature,1997,390:417-21.
[58]Li X, Shimada K, Showalter LA et al. Biophysical properties of C1C-3 differentiate it from swelling-activated chloride channels in Chinese hamster ovary-K1 cells [J]. J Biol Chem,2000,275:35994-8.
[59]Stobrawa SM, Breiderhoff T, Takamori S, et al. Disruption of C1C-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus [J]. Neuron,2001,29:185-96.
[60]Al-Awqati Q. Chloride channels of intracellular organelles [J]. Curr Opin Cell Biol,1995,7:504-8.
[61]Szewczyk A. The intracellular potassium and chloride channels:properties, pharmacology and function [J]. Mol Membr Biol,1998,15:49-58.
[62]Woodbury DJ. Evaluation of the evidence for ion channels in synaptic vesicles [J]. Mol Membr Biol,1995,12:165-71.
[63]Maycox PR, Deckwerth T, Hell JW, et al. Glutamate uptake by brain synaptic vesicles. Energy dependence of transport and functional reconstitution in proteoliposomes [J]. J Biol Chem,1988,263:15423-8.
[64]Stobrawa SM, Breiderhoff T, Takamori S, et al. Disruption of C1C-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus [J]. Neuron,2001,29:185-96.
[65]Yamashiro DJ, Maxfield FR.J. Acidification of morphologically distinct endosomes in mutant and wild-type Chinese hamster ovary cells [J]. Cell Biol, 1987,105(6 Pt 1):2723-33.
[66]Moore HP, Andresen JM, Eaton BA, et al. Biosynthesis and secretion of pituitary hormones:dynamics and regulation [J]. Arch Physiol Biochem,2002,110(1-2): 16-25.
[67]Machen TE, Chandy G, Wu M, et al. Cystic fibrosis transmembrane conductance regulator and H+ permeability in regulation of Golgi pH [J]. JOP,2001,2(4 Suppl):229-36.
[68]Nishi T, Forgac M. The vacuolar (H+)-ATPases--nature's most versatile proton pumps [J]. Nat Rev Mol Cell Biol,2002,3(2):94-103.
[69]Grabe M, Oster G.J. Regulation of organelle acidity [J]. Gen Physiol, 2001,117(4):329-44.
[70]Brown D, Paunescu TG, Breton S, et al. Regulation of the V-ATPase in kidney epithelial cells:dual role in acid-base homeostasis and vesicle trafficking [J]. J Exp Biol,2009,212(Pt 11):1762-72.
[71]Devuyst O. Chloride channels and endocytosis:new insights from Dent's disease and CLC-5 knockout mice [J]. Bull Mem Acad R Med Belg,2004,159(Pt 2):212-7.
[72]Hara-Chikuma M, Yang B, Sonawane ND, et al. C1C-3 chloride channels facilitate endosomal acidification and chloride accumulation [J]. J Biol Chem, 2005,280(2):1241-7.
[73]Li DQ, Jing X, Salehi A, et al. Suppression of sulfonylurea- and glucose-induced insulin secretion in vitro and in vivo in mice lacking the chloride transport protein C1C-3 [J]. Cell Metab,2009,10:309-15.
[74]Deriv LV, Gomez EA, Jacobson DA, et al. The granular chloride channel C1C-3 is permissive for insulin secretion [J]. Cell Metab,2009,10:316-23.
[75]Song C, Duan XQ, Zhou Y, et al. Experimental study on islet cells in rats under condition of three-dimensional microgravity [J]. Zhonghua Wai Ke Za Zhi,2004, 42(9):559-61.
[76]Chang XB. Molecular mechanism of ATP-dependent solute transport by multidrug resistance-associated protein 1 [J]. Methods Mol Biol,2010, 596:223-49.
[77]Breedveld P, Benjnen JH, Schellens JHM. Use of P-glycoprotein and BCRP inhibitors to improve oral bioavailability and CNS penetration of anticancer drugs [J]. Trends Pharmacol Sci,2006,27:17—24.
[78]Vanoye CG, Castro AF, Pourcher T, et al Phosphorylation of P-glycoprotein by PKA and PKC modulates swelling-activated Cl- currents [J]. Am J physiol,1999, 276:370-8.
[79]Chinn LW, Kroetz DL. ABCB1 pharmacogenetics:progress, pitfalls, and promise [J]. Clin Pharmacol Ther,2007,81(2):265-9.
[80]Kawai K, Kusano I, IdoM, et al. Identification of a P-Glycoprotein-Related protein (mini-P-glycoprotein) overexpressed in multidrug resistant cells [J]. Biochem Biophys Res Commun,1994,198(2):804-10.
[81]Oselin K, Nowakowski-Gashaw I, Mrozikiewicz PM, et al. Quantitative determination of MDR1 mRNA expression in peripheral blood lymphocytes:a possible role of genetic polymorphisms in the MDR1 gene [J]. Eur J Clin Invest, 2003,33(3):261-7.
[82]Rosengren AH, Jokubka R, Tojjar D, et al. Overexpression of alpha2A-adrenergic receptors contributes to type 2 diabetes [J].Science,2010,327(5962):217-20.
[83]Bartlett MS, Stirling D. A Short History of the Polymerase Chain Reaction [J]. Methods Mol Biol,2003,226:3-6.
[84]Purves. Life:The Science of Biology [M]. USA:Freeman and Company,2001: 214-217.
[85]Michael W. Pfaffl. A new mathematical model for relative quantification in real-time RT-PCR [J]. Nucleic Acids Research,2001,29:9 e45.
[86]Frederique Ponchel, Carmel Toomes, Kieran Bransfield, et al. Real-time PCR based on SYBR-Green I fluorescence:An alternative to the TaqMan assay for a relative quantification of gene rearrangements, gene amplifications and micro gene deletions [J]. BMC Biotechnology,2003,3:18.
[87]H Maeda, C Fujimoto, Y Haruki, et al. Quantitative real-time PCR using TaqMan and SYBR Green for Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, tetQ gene and total bacteria [J]. FEMS Immunol Med Microbiol,2003,39(1):81-6.
[88]Hammond S M, Bernstein E, Beach D, et al. An RNA-directed nuclease mediates posttranscription algene silencing in Drosophila cells [J]. Nature, 2000,404(6775):293-6.
[89]Bernstein E, Caudy A A, Hammond S M, et al. Role for a bidentate ribo nuclease in the initiation step of RNA interference [J]. Nature,2001, 409(6818):363-6.
[90]Yang D, Lu H, Erickson JW. Evidence that processed small dsRNAs may mediate sequence-specific mRNA degradation during RNAi in Drosophlia embryos [J]. CurrBio,2000,1(19):1191-200.
[91]Fire A. RNA triggered gene silencing [J]. TIG,1999,15:358-61.
[92]Kawasaki H, Taira K. Short hairpin type of dsRNAs that are controlled by tRNA(Val) promoter significantly induce RNAi mediated gene silencing in the cytoplasm of human cells [J]. Nucleic Acids Res,2003,31:700-7.
[93]Caplen NJ, Fleenor J, Fire A, et al. dsRNA-mediated gene silencing in cultured Drosophila cells [J]. Gene,2000,252:95-105.
[94]Fire A, Xu S, Montgomery MK, et al. Potent and specific genetic interference by dsRNA in caenorhabditis elegans [J]. Nature,1998,391:806-11.
[95]Zamre PD, Tuschl T, Sharp PA, et al. RNAi dsRNA directs the ATP dependent cleavage of mRNA at 21 to 23 nucleotide intervals [J]. Cell,1999,101:25-33.
[96]朱睿,张开立,邹向阳.RNA干扰(RNAi)技术及其在功能基因组学研究中的应用[J].大连医科大学学报,2003,25(2)：15-7.
[97]Brenner C, Kroener G. Apoptosis:Mitochondria--the death cell integrators [J]. Science,2000,289:1150-1.
[98]Guerrero I, Ruiz i Altaba A. Development. Longing for ligand:hedgehog, patched, and cell death [J]. Science,2003,301 (5634):774-6.
[99]Wajant H. The Fas signaling pathway:more than a paradigm [J]. Science,2002, 296 (5573):1635-6.
[100]Salvesen GS. Caspases and apoptosis [J]. Essays Biochem,2002,38:9-19.
[101]Johnstone RW, Ruefli AA, Smyth MJ. Multiple physiologicl functions for multidrug transporter P-glycoprotein [J]. Trends Biochem Sci,2000,25(1):1-6.
[102]Smyth MJ, Krasovskis E, Sutton VR, et al. The drug efflux protein, P-glycoprotein, additionally protects drug-resistant tumor cells from multiple form of caspase-dependent apoptosis [J]. Proc Nati Acad Sci,1998,95(12): 7024-29.
[103]Gollapudi S, Gupta S. Anti-P-glycoprotein antibody induced apoptosis of activated peripheral blood lymphocytes:a possible role of P-glycoprotein in lymphocyte survival [J]. J Clin Immunol,2001,21(6):420-30.
[104]Cullen KV, Davey RA, Davey MW. Drug resistance does not correlate with resistance to Fas-mediated apoptosis [J]. Leuk Res,2001,25(1):69-75.
[105]Trindade GS, Capella LS, Affonso M, et al. Differences in sensitivity to UVC, UVB and UVC radiation of a multidrug-resistant cell line overexpressing P-glycoprotein [J]. Photochem Photobiol,1999,69(6):694-9.
[106]Ruth AC, Roninson IB. Effects of the multidrug transporter P-glycoprotein on cellular responses to ionizing radiation [J]. Cancer Res,2000,60(10):2576-8
[107]陈俊,张积仁,肖明星,等.P糖蛋白抑制X射线诱导凋亡及对线粒体膜电位的影响[J].中华放射医学与防护杂志,2004,24(4)：297-9.
[108]Ruefli AA, Tainton KM, Darey PK, et al. P-glycoprotein inhibits caspase-8 activation but not formation of the death inducing signal complex (disc) following Fas ligation [J]. Cell Death Differ,2002,9(11):1266-72.
[109]Larsen AK, Escargueil AE, Skladanowski A. Resistance mechanisms associated with altered intracellular distribution of anticancer agents [J]. Pharmacol Ther, 2000,85(3):217-29.
[110]Marquardt D, Center MS. Involvement of vascular H+-adenosine triphoshatase activity in multidrug resesistance HL60 cells [J]. J Natl Cancer Inst,1991, 83(15):1098-102.
[111]Segal MS, Beem E. Effect of pH, ionic charge, and osmolality on cytochrome c-mediated caspase-3 activity [J]. Am J Physiol Cell Physiol,2001,281(4): C1196-204.
[112]Robinson LJ, Roberts WK, LingT T, et al. Human MDR1 protein overexpression delays the apoptotic cascade in Chinese hamster ovary fibroblast [J]. Biochemistry,1997,36(37):11169-78.
[113]Idriss HT, Hunnun YA, Boulpaep E, et al. Regulation of volume-activated channels by P-glycoprotein:phosphorylatin has the final say [J]. J Physiol,2000, 524(3):629-36.
[114]Bezombes C, Maestre N, Laurent G, et al. Restoration of TNF-alpha-induced ceramide generation and apoptosis in resistant human leukemia KG1a cells by the P-glycoprotein blocker PSC833 [J]. FASEB J,1998,12(1):101-9.
[115]Lucci A, ChoWI, Han TY, et al. Glucosylceramide:a marker for multiple-drug resistant cancers [J]. Anticancer Res,1998,18(1B):475-80.
[116]Lavie Y, Cao HT, Volner A, et al. Agents that reverse multidrug resistance, tamoxifen, verapamil, and cyclosporin A, block glycosphingolipid metabolism by inhibiting ceramide glycosylation in human cancer cells [J]. J Biol Chem, 1997,272(3):1682-7.
[117]Sathiyapriya V, Bobby Z, Agrawal A, et al. Protein glycation, insulin sensitivity and pancreatic beta cell function in high-risk, non-diabetic, first degree relatives of patients with type 2 diabetes [J]. Indian J Physiol Pharmacol,2009, 53(2):163-8.
[118]Mulder H, Ling C. Mitochondrial dysfunction in pancreatic beta-cells in Type 2 diabetes [J]. Mol Cell Endocrinol,2009,297(1-2):34-40.
[119]Wajchenberg BL.Beta-cell failure in diabetes and preservation by clinical treatment [J]. Endocr Rev,2007,28(2):187-218.
[120]Wan J, Jiang L, Lu Q, et al. Activation of PPARdelta up-regulates fatty acid oxidation and energy uncoupling genes of mitochondria and reduces palmitate-induced apoptosis in pancreatic beta-cells [J]. Biochem Biophys Res Commun,2010,391(3):1567-72.
[121]Del Prato S. Role of glucotoxicity and lipotoxicity in the pathophysiology of Type 2 diabetes mellitus and emerging treatment strategies [J]. Diabet Med, 2009,26(12):1185-92.
[122]Clark A, Wells CA, Buley ID, et al. Islet amyloid, increased A-cells, reduced B-cell and exocrine fibrosis:quantitative changes in the pancreas in type 2 diabetes [J]. Diabetes Res,1988,9(4):151-9.
[123]Janson J, Ashley RH, Harrison D, et al. The mechanism of islet amyloid polypeptide toxicity is membrane disruption by intermediate-sized toxic amyloid particles [J]. Diabetes,1999,48:491-8.
[124]Janciauskiene S, Ahren B. Fibrillar islet amyloid polypeptide differentially affects oxidative mechanisms and lipoprotein uptake in correlation with cytotoxicity in two insulin-producing cell lines [J]. Biochem Biophys Res Commun,2000,267:619-25.
[125]Ajabnoor MA, EI-Naggar MM, Elayat AA, et al.. Functional and morphological study of cultured pancreatic islets treated with cyclosporine [J]. Life Sci,2007, 80:345-55.
[126]Gottesman M M, Fojo T, Bates S E. Multidrug resistance in cancer:role of ATP-dependent transporters [J]. Nat Rev Cancer,2002,2:48-58.
[127]Gottesman M M, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter [J]. Ann Rev Biochem,1993,62:385-427.
[128]Witherspoon S M, Emerson D L, Kerr B M, et al. Flow cytometric assay of modulation of P-glycoprotein function in whole blood by the multidrug resistance inhibitor GG918 [J]. Clin Cancer Res,1996,2:7-12.
[129]Ferry D R, Traunecker H, Kerr D J. Clinical trials of P-glycoprotein reversal in solid tumours [J]. Eur J Cancer,1996,32A:1070-1081.
[130]Baumert C, Hilgeroth A. Recent advances in the development of P-gp inhibitors[J]. Anticancer Agents Med Chem,2009,9(4):415-36.
[131]Hjelmasaeth J, Hagen LT, Asberg A, et al. The impact of short-term cyclosporin A treatment on insulin secretion and insulin sensitivity in man [J]. Nephrol Dial Transplant,2007,22(6):1743-9.
[132]Montori VM, Basu A, Erwin PJ, et al. Posttransplantation diabetes:a systematic review of the literature[J]. Diabetes Care,2002,25:583-92.
[133]van Duijnhoven EM, Boots JMM, Christiaans MHL, et al. Influence of tacrolimus on glucose metabolism before and after renal transplantation:a prospective study[J]. J Am Soc Nephrol,2001,12:583-8.
[134]Robertson RP, Franklin G, Nelson L. Intravenous glucose tolerance and pancreatic islet beta-cell function in patients with multiple sclerosis during 2-yr treatment with cyclosporin[J]. Diabetes,1989,38:58-64.
[135]Nam JH, Mun JI, Kim SI, et al. Beta-Cell dysfunction rather than insulin resistance is the main contributing factor for the development of postrenal transplantation diabetes mellitus[J]. Transplantation,2001,71:1417-23.
[136]SatoT, Inagaki A, Uchida K, et al. Diabetes mellitus after transplant:relationship to pretransplant glucose metabolism and tacrolimus or cyclosporine A-based therapy[J]. Transplantation,2003,76:1320-6.
[137]Caumo A and Luzi L. First-phase insulin secretion:does it exist in real life? Considerations on shape and function [J]. Am J Physiol Endocrinol Metab,2004, 287:E371-8.
[138]Doyle ME, Egan JM. Pharmacological agents that directly modulate insulin secretion [J]. Pharmacol Rev,2003,55:105-131.
[139]Oetjen E, Thoms KM, Laufer Y, et al. The immunosuppressive drugs cyclosporin A and tacrolimus inhibit membrane depolarization-induced CREB transcriptional activity at the coactivator level [J]. Br J Pharmacol,2005, 144:982-93.
[140]Schwaninger M, Blume R, Oetjen E, et al. Inhibition of cAMP-responsive element-mediated gene transcription by cyclosporin A and FK506 after membrane depolarization [J]. J Biol Chem,1993,268:23111-5.
[141]Lawrence MC, Bhatt HS, Watterson JM, et al. Regulation of insulin gene transcription by a Ca(2+)-responsive pathway involving calcineurin and nuclear factor of activated T cells [J]. Mol Endocrinol 2001,15:1758-67.
[142]Lawrence MC, Bhatt HS, Easom RA. NFAT regulates insulin gene promoter activity in response to synergistic pathways induced by glucose and glucagon-like peptide-1 [J]. Diabetes,2002,51:691-8.
[143]Konrad T, Steinmuller T, Vicini P, et al. Regulation of glucose tolerance in patients after liver transplantation:impact of cyclosporin versus tacrolimus therapy [J]. Transplantation,2000,69:2072-8.
[144]Dresner LS, Andersen DK, Kahng KU, et al. Effects of cyclosporine on glucose metabolism [J]. Surgery,1989,106:163-9.
[145]Bratanova-Tochkova TK, Cheng H, Daniel S, et al. Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion [J]. Diabetes,2002, 51(Suppl_1):S83-S90.
[146]Donelan MJ, Morfini G, Julyan R, et al. Ca2+-dependent dephosphorylation of kinesin heavy chain on beta-granules in pancreatic beta-cells. Implications for regulated beta-granule transport and insulin exocytosis [J]. J Biol Chem,2002, 277:24232-42.
[147]Drachenberg CB, Klassen DK, Weir MR, et al. Islet cell damage associated with tacrolimus and cyclosporine:morphological features in pancreas allograft biopsies and clinical correlation [J]. Transplantation,1999,68:396-402.
[148]Nielsen JH, Mandrup-Poulsen T, Nerup J. Direct effects of cyclosporin A on human pancreatic beta-cells [J]. Diabetes,1986,35:1049-52.
[149]Fuhrer DK, Kobayashi M, Jiang H. Insulin release and suppression by tacrolimus, rapamycin and cyclosporin A are through regulation of the ATP-sensitive potassium channel [J]. Diabetes Obes Metab,2001,3:393-402.
[150]Ebihara K, Fukunaga K, Matsumoto K, et al. Cyclosporin A stimulation of glucose-induced insulin secretion in MIN6 cells [J]. Endocrinology,1996,137: 5255-63.
[1]韩贻仁.分子细胞生物学[M].北京：科学出版社,2001：126.
[2]孙大业,马力耕,崔素娟.细胞信号转导[M].北京：科学出版社,2001：228.
[3]李俊敏,刘朝晖,尚忠林.细胞膜上的离子通道[J].河北师范大学学报(自然科学版),2005,29：519-22.
[4]张宗明,裘法祖.离子通道与疾病[J].World Chin J Digestol,2005,13(5)：585-7.
[5]Hatta S, Sakamoto T, Horio Y. Ion channels and diseases[J]. Med Electron M icrosc,2002,35:117-26.
[6]张晓东,臧益民,周士胜等.CIC通道的生物学及相关疾病[J].生理科学进展,2001,32(4)：327-30.
[7]Jentsch TJ, Friedrich T, Schrier A, et al. The C1C chloride channel family [J]. Eur J Physiol,1999,437:783-95.
[8]张晓东,臧益民,周士胜.心脏氯离子通道研究进展[J].心脏杂志,2000,12：473-7.
[9]Fahlke C, Rhodes TH, Desai RR, et al. Pore sloiehiomet of a voltage-gated chloride chmnnel [J]. Nature,1998,394:687-90.
[10]Saviance C, Conli F, Pusch M. The muscle chloride channel C1C-1 has double barreled appearance that is differently affected in dominant and recessive myotonia [J]. J Fen Physio 1,1999,113:457-67.
[11]Jentsch TJ, Steinmeyer K, Schwarz G. Primary structure of Torpedo mamorata chloride channel isolated by expression cloning in Xenopus oocytes [J]. Nature, 1990,348:510-4.
[12]Kawasaki M, Uchida S, Monkawa T, et al. Cloning and expression of a protein C-regulated chloride channel abundantly expressed in rat brain neuronal ceils [J]. Neuron,1994,12:597-604.
[13]Borsani G, Rugarli El, Taglialatela M, et al. Characterization of a human and murine gene (CLCN3) sharing similarities to voltage-gated chloride channels and to a yeast integral membrane protein [J]. Genomics,1995,27:131-41.
[14]Vogalis F, Vincent T, Oureshi I, et al. Cloning and expression of the large-conductance Ca2+-activated K+ channel from colonic smooth muscle [J]. Am J Physiol,1996,271:G629-39.
[15]Britton FC, Hatton WJ, Rossow CF, et al. Molecular distribution of volume-regulated chloride channels (C1C-2 and CIC—3) in cardiac tissues [J]. Am J Physiol Heart Circ Physiol,2000,279(5):H2225-33.
[16]Shimada K, Li X, Xu G, et al. Expresion and canalicular localization of two isoforms of the CIC-3 chloride channel from rat hepatocytes [J]. Am J Physiol Gastrointest Liver Physiol,2000,279(2):G268～76.
[17]Huang P, Liu J, Di A, et al. Regulation of human CIC-3 channels by multifunctional Ca2+ /calmodulin dependent protein kinase [J]. J Biol Chem, 2001,276(23):20093-100.
[18]Duan D, W inter C, Cowley S, et al. Molecular identification of a volume regulated chloride channel [J]. Nature,1997,390(6658):417-21.
[19]Duan D, Cowley S, Horowitz B, et al. A serine residue in CIC-3 links phosphorylation-dephosphorylation to chloride channel regulation by cell volume [J]. J Gen Physiol,1999,113(1):57-70.
[20]Li X, Shimada K, Showalter LA, et al. Biophysical properties of CIC-3 differentiate it from swelling-activated chloride channels in Chinese hamster ovary-KI cells [J]. J Biol Chem,2000,275(46):35994-8.
[21]Dick GM, Bradley KK, Horowitz B, et al. Functional and molecular identification of a novel chloride conductance in canine colonic smoth muscle [J]. Am J Physiol,1998,275(4 Pt 1):C940-50.
[22]von Weikersthal SF, Barrand MA, Hladky SB. Functional and molecular characterization of a volume-sensitive chloride current in rat brain endothelial cells [J]. J Physiol,1999,516(Pt 1):75-84.
[23]Wang L, ChenL, JacobTJ. The role of CIC-3 in volume-activated chloride currents and volume regulation in bovine epithelial cells demonstrated by antisense inhibition [J]. J Physiol,2000,524(Pt1):63-75.
[24]Duan D, Zhong J, Hermoso M, et al. Functional inhibition of native volume-sensitive outwardly rectifying anion chanels in muscle cells and Xenopus oocytes by anti-C1C-3 antibody [J]. J Physiol,2001,531(Pt 2): 437-44.
[25]Tseng GN. Cell sweling increases membrane conductance of canine cardiac cells:Evidence for a volume-sensitive Cl channel [J]. Am J Physiol,1992,262(4 Pt 1):C1056-68.
[26]Sorota S. Swelling-induced chloride-sensitive current in canine a trial cells revealed by whole-cell patch-clamp method [J]. Circ Res,1992,70(4):679-87.
[27]Kawasaki M, Suzuki M, Uchida S, et al. Stable and functional expression of the C1C-3 chloride channel in somatic cell lines [J]. Neuron,1995,14(6):1285-91.
[28]Keenan C, Kelleher D. Protein kinase C and the cytoskeleton [J]. Cell Signal, 1998,10(4):225-32.
[29]Hume JR, Duan D, Collier ML, et al. Anion transport in heart [J]. Physiol Rev, 2000,80(1):31-81.
[30]Obermuller N, Gretz N, Kriz W, et al. The swelling-activated chloride channel CIC-2, the chloride channel CIC-3. and CIC-5, a chloride channel mutated in kidney stone disease, are expressed in distinct subpopulations of renal epithelial cells [J]. J Clin Invest,1998,101(3):635-42.
[31]Stobrawa SM, Breiderhoff T, Takamori S, et al. Disruption of CIC-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus [J]. Neuron,2001,29(1):185-96.
[32]Kinard TA, Goforth PB, Tao Q, et al. Chloride channels regulate HIT cell volume but cannot fully account for swelling-induced insulin secretion [J]. Diabetes,2001,50(5):992-1003.
[33]Weylandt KH, Valverde MA, Nobles M, et al. Human CIC-3 is not the swelling-activated chloride channel involved in cell volume regulation [J]. J Biol Chem,2001,276(20):17461-7.
[34]Du XY, Sorota S. Protein kinase C stimulates swelling-induced chloride current in canine atrial cells [J]. Pflugers Arch,1999,437(2):227-34.
[35]Waldegger S, Barth P, Raber G, et al. Cloning and characterization of a putative human serine/threonine protein kinase transcriptionally modified during anisotonic and isotonic alterations of cell volume [J]. Proc Nalt Acad Sci,1997, 94:4440-5.
[36]Frank Thevenod. Ion channels in secretary granules of the pancreas and their role in exocytosis and release of secretory proteins [J]. Am J Physiol Cell Physiol, 2002,283:C651-C672.
[37]Bokvist K, Holmqvist M, Gromada J, et al. Compound exocytosis in voltage-clamped mouse pancreatic beta-cells revealed by carbon fibre amperometry [J]. Pflu" gers Arch,2000,439:634-45.
[38]Bosl MR, Stein V, Hubner C, et al. Male germ cells and photoreceptors, both dependent on close cell-cell interactions, degenerate upon C1C-2 Cl- channel disruption [J]. EMBO J,2001,20:1289-99.
[39]Duan D, Cowley S, Horowitz B, et al. A serineresidue in C1C-3 links phosphorylation-dephosphorylation to chloride channel regulation by cell volume [J]. J Gen Physiol,1999,113:57-70.
[40]Duan D, Winter C, Cowley S, et al. Molecular identification of a volume-regulated chloride channel [J]. Nature,1997,390:417-21.
[41]Li X, Shimada K, Showalter LA, et al. Biophysical properties of C1C-3 differentiate it from swelling-activated chloride channels in Chinese hamster ovary-Kl cells [J]. J Biol Chem,2000,275:35994-8.
[42]Stobrawa SM, Breiderhoff T, Takamori S, et al. Disruption of C1C-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus [J]. Neuron,2001,29:185-96.
[43]Al-Awqati Q. Chloride channels of intracellular organelles [J]. Curr Opin Cell Biol,1995,7:504-8.
[44]Szewczyk A. The intracellular potassium and chloride channels:properties, pharmacology and function [J]. Mol Membr Biol,1998,15:49-58.
[45]Woodbury DJ. Evaluation of the evidence for ion channels in synaptic vesicles [J]. Mol Membr Biol,1995,12:165-71.
[46]Maycox PR, Deckwerth T, Hell JW, et al. Glutamate uptake by brain synaptic vesicles. Energy dependence of transport and functional reconstitution in proteoliposomes [J]. J Biol Chem,1988,263:15423-8.
[47]Stobrawa SM, Breiderhoff T, Takamori S, et al. Disruption of C1C-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus [J]. Neuron,2001,29:185-96.
[48]Barg S, Huang P, Eliasson L, et al. Priming of insulin granules for exocytosis by granular Cl- uptake and acidification [J]. J Cell Sci,2001,114:2145-54.
[49]Corkey BE, Deeney JT, Yaney GC, et al. The role of long-chain fatty acyl-CoA esters in beta-cell signal transduction [J]. J Nutr,2000,130:299S-304S.
[50]Deeney JT, Prentki M, Corkey BE. Metabolic control of beta-cell function [J]. Semin Cell Dev Biol,2000,11:267-75.
[51]Ashcroft FM, Rorsman P. Electrophysiology of the pancreatic beta-cell [J]. Prog Biophys Mol Biol,1989,54:87-143.
[52]Lang J. Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrine secretion [J]. Eur J Biochem,1999,259:3-17.
[53]Hutton JC. Insulin secretory granule biogenesis and the proinsulin-processing endopeptidases [J]. Diabetologia,1994,37:S48-S56.
[54]Jahn R, Su" dhof TC. Membrane fusion and exocytosis [J]. Annu Rev Biochem, 1999,68:863-911.
[55]Eliasson L, Renstrom E, Ding WG, et al. Rapid ATP-dependent priming of secretory granules precedes Ca2+-induced exocytosis in mouse pancreatic B-cells [J]. J Physiol,1997,503:399-412.
[56]Renstrom E, Eliasson L, Bokvist K, et al.Cooling inhibits exocytosis in single mouse pancreatic B-cells by suppression of granule mobilization [J]. J Physiol, 1996,494:41-52.
[57]Hou JC, Min L, Pessin JE. Insulin granule biogenesis, trafficking and exocytosis [J]. Vitam Horm,2009,80:473-506.
[58]Del Prato S, Marchetti P, Bonadonna RC. Phasic insulin release and metabolic regulation in type 2 diabetes [J]. Diabetes,2002,51:S109-116.
[59]Rorsman P, Eliasson L, Renstrom E, et al. The cell physiology of biphasic insulin secretion [J]. News Physiol Sci,2000,15:72-7.
[60]Porte D Jr. Banting lecture 1990. Beta-cells in type Ⅱ diabetes mellitus [J]. Diabetes,1991,40:166-80.
[61]Henquin JC. The fiftieth anniversary of hypoglycaemic sulphonamides. How did the mother compound work [J]? Diabetologia,1992,35:907-12.
[62]Ashcroft SJ, Niki I, Kenna S, et al. The beta-cell sulfonylurea receptor [J]. Adv Exp Med Biol,1993,334:47-61.
[63]Trube G, Rorsman P, Ohno-Shosaku T. Opposite effects of tolbutamide and diazoxide on the ATP-dependent K+channel in mouse pancreatic beta-cells [J]. Pflu" gers Arch,1986,407:493-9.
[64]Aguilar-Bryan L, Nichols CG, Wechsler S, et al. Cloning of the beta-cell high-affinity sulfonylurea receptor:a regulator of insulin secretion [J]. Science, 1995,268:423-6.
[65]De Lisle RC, Schulz I, Tyrakowski, et al. Isolation of stable pancreatic zymogen granules [J]. Am J Physiol Gastrointest Liver Physiol,1984,246:G411-8.
[66]Litman T, Druley TE, Stein WD, et al. From MDR to MXR:new understanding of multidrug resistance systems, their properties and clinical significance [J]. Cell Mol Life Sci,2001,58:931-59.
[67]Inagaki N, Gonoi T, Clement JP, et al. Reconstitution of KATP:an inward rectifier subunit plus the sulfonylurea receptor [J]. Science,1995,270:1166-70.
[68]Carpentier JL, Sawano F, Ravazzola M, et al. Internalization of 3H-glibenclamide in pancreatic islet cells [J]. Diabetologia,1986,29:259-61.
[69]Ozanne SE, Guest PC, Hutton J, et al. Intracellular localization and molecular heterogeneity of the sulphonylurea receptor in insulin-secreting cells [J]. Diabetologia,1995,38:277-82.
[70]Palade G, Szewczyk A. Intracellular targets for antidiabetic sulfonylureas and potassium channel openers [J]. Biochem Pharmacol,1997,54:961-5.
[71]Eliasson L, Renstrom E, Ammala C, et al. PKC-dependent stimulation of exocytosis by sulfonylureas in pancreatic beta-cells [J]. Science,1996,271: 813-5.
[72]The'venod F, Anderie I, Schulz I. Monoclonal antibodies against MDR1 P-glycoprotein inhibit chloride conductance and label a 65-kDa protein in pancreatic zymogen granule membranes [J]. J Biol Chem,1994,269:24410-7.
[73]The'venod F, Chathadi KV, Jiang B, et al. ATPsensitive K+conductance in pancreatic zymogen granules:block by glyburide and activation by diazoxide [J]. J Membr Biol,1992,129:253-66.
[74]The'venod F, Hildebrandt JP, Striessnig J, et al. Chloride and potassium conductances of mouse pancreatic zymogen granules are inversely regulated by a approximately 80-kDa mdrla gene product [J]. J Biol Chem,1996, 271:3300-5.
[75]Barg S, Renstro"m E, Berggren PO, et al. The stimulatory action of tolbutamide on Ca2+-dependent exocytosis in pancreatic cells is mediated by a 65 kDa mdr-like P-glycoprotein [J]. Proc Natl Acad Sci,1999,96:5539-44.
[76]Shindo T, Yamada M, Isomoto S, et al. SUR2 subtype (A and B)-dependent differential activation of the cloned ATP-sensitive K+ channels by pinacidil and nicorandil [J]. Br J Pharmacol,1998,124:985-91.
[77]Dunne MJ, Petersen OH. Intracellular ADP activates K+channels that are inhibited by ATP in an insulin-secreting cell line [J]. FEBS Lett,1986,208: 59-62.
[78]Kakei M, Kelly RP, Ashcroft SJ, et al. The ATP-sensitivity of K+channels in rat pancreatic B-cells is modulated by ADP [J]. FEBS Lett,1986,208:63-6.
[79]Misler S, Falke LC, Gillis K, et al. A metabolite-regulated potassium channel in rat pancreatic B cells [J]. Proc Natl Acad Sci,1986,83:7119-23.
[80]Braun M, Anderie I, The'venod F. Evidence for a 65 kDa sulfonylurea receptor in rat pancreatic zymogen granule membranes [J]. FEBS Lett,1997,411:255-9.
[81]The'venod F, Chathadi KV, Jiang B, et al. ATPsensitive K+conductance in pancreatic zymogen granules:block by glyburide and activation by diazoxide [J]. J Membr Biol,1992,129:253-66.
[82]Kirk J, Syed SK, Harris AL, et al. Reversal of P-glycoproteinmediated multidrug resistance by pure anti-oestrogens and novel tamoxifen derivatives [J]. Biochem Pharmacol,1994,48:277-85.
[83]Sutton RB, Fasshauer D, Jahn R, et al. Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 (?) resolution [J]. Nature,1998,395: 347-53.
[84]Ungermann C, Wickner W, Xu Z. Vacuole acidification is required for trans-SNARE pairing, LMA1 release, and homotypic fusion [J]. Proc Natl Acad Sci,1999,96:11194-9.
[85]De Lisle RC, Williams JA. Zymogen granule acidity is not required for stimulated pancreatic protein secretion [J]. Am JPhysiol Gastrointest Liver Physiol,1987,253:G711-9.
[86]Curry DL, Bennett LL, Grodsky GM:Dynamics of insulin secretion by the perfused rat pancreas [J]. Endocrinology,1968,83(3):572-84.
[87]Henquin JC, Nenquin M, Stiernet P, et al. In Vivo and In Vitro Glucose-Induced Biphasic Insulin Secretion in the Mouse:Pattern and Role of Cytoplasmic Ca2+ and Amplification Signals in {beta}-Cells [J]. Diabetes,2006,55(2):441-51.
[88]Fehse F, Trautmann M, Holst JJ, et al. Exenatide augments firstand second-phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes [J]. J Clin Endocrinol Metab,2005,90(11):5991-7.
[89]Jiaqiang Ren, Ping Jin, Ena Wang, et al. Pancreatic islet cell therapy for type I diabetes:understanding the effects of glucose stimulation on islets in order to produce better islets for transplantation [J]. Journal of Translational Medicine, 2007,5:1-15.
[90]Kwan EP, Gaisano HY. Glucagon-like peptide 1 regulates sequential and compound exocytosis in pancreatic islet betacells [J]. Diabetes,2005,54(9): 2734-43.
[91]Bratanova-Tochkova TK, Cheng H, Daniel S, et al. Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion [J]. Diabetes,2002, 51(Suppl 1):S83-90.
[92]Rorsman P, Renstrom E:Insulin granule dynamics in pancreatic beta cells [J]. Diabetologia,2003,46(8):1029-45.
[93]Daniel S, Noda M, Straub SG, et al. Identification of the docked granule pool responsible for the first phase of glucose-stimulated insulin secretion [J]. Diabetes,1999,48(9):1686-90.
[94]兰李,周云燕,杨志勇等.活细胞钙离子浓度荧光显微检测系统的研制和应用[J].生物医学工程研究,2004,23：114-7.
[95]Chorbachi R, Graham JM, Ford J, et al. Cochlear implantation in Jervell and Lange—Nielsen syndrome [J]. Int J Pediatr Otorhinolaryngol,2002,66:213— 21.
[96]Hosaka Y, Hanawa H, Washizuka T, et al. Function subcellular localization and assembly of a novel mutation of KCNJ2 in Andersen s syndrome [J]. J Mol Cell Cardiol,2003,35:409-15.
[97]Swift PA, MacGregor GA. The epithelial sodium channel in hypertension: genetic heterogeneity and implications for treatment with amiloride [J]. Am J Pharmacogenomics,2004,4:161-8.
[98]Spampanato J, Keamey JA, de Haan G, et al. A novel epilepsy mutation in the sodium channel SCN 1A identifies a cytoplasmic domain for beta subunit interaction [J]. J Neurosci,2004,24:10022-34.
[99]Nishimune H, Sanes IR, Carlson SS. A synaptic laminin-calcium channel interaction organizes active zones in motor new eterminals [J]. Nature,2004, 432:580-7.
[100]Waldegger S, lentsch. Functional and structural analysis of C1C-K chloride channels involved in renal disease [J]. J Biol Chem,2000,275:24527—33.