KCI和forskolin诱导的神经元CCK、PPT、PDYN表达协同上调及其与PACAP、BDNF相互作用研究
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摘要
神经元内垂体腺苷酸环化酶激活多肽(Pituitary adenylate cyclase-activating polypeptide, PACAP)基因表达可被Ca2+内流及细胞内cAMP信号增强协同升高,参与调节突触可塑性及情感调控等多种生理功能。脑源性神经营养因子(Brain-derived neurotrophic factor, BDNF)表达受PACAP调节,在促进神经元存活、分化及突触可塑性方面起重要作用。强啡肽原(Prodynorphin, PDYN)基因、胆囊收缩素(Cholecystok inin,CCK)基因、前速激肽原(Preprotachykinin, PPT)基因编码的蛋白也参与中枢神经系统多种功能的调控过程。研究发现,KC1与腺苷酸环化酶激活剂forskolin共同作用协同升高PACAP基因表达,升高BDNF基因表达水平但无协同作用。然而,PACAP及BDNF作为内源性物质,与PDYN、CCK、PPT基因表达之间是否相互影响,以及如何相互影响,还不是很清楚。为此,本文研究了Ca2+内流及细胞内cAMP信号增强引起的神经元内基因表达变化及PDYN、CCK、PPT与PACAP、BDNF相互影响。在发现PACAP诱导PDYN表达的基础上,着重探讨了其潜在的作用机制。
本文采用KC1与腺苷酸环化酶激活剂forskolin共同作用于原代培养的大鼠皮层神经元,分别引起神经元去极化进而诱导Ca2+内流及细胞内cAMP信号增强,通过基因芯片技术、定量RT-PCR方法检测大鼠皮层神经元内PDYN基因、CCK基因及PPT基因的表达水平；并进一步采用定量RT-PCR及细胞免疫荧光技术研究了PACAP对PDYN、 BDNF等基因表达的影响与机制。
研究发现,KCl与forskolin升高包括PDYN、CCK、PPT基因在内的62种基因至其基础表达水平3倍以上；协同升高神经元内PDYN、CCK、PPTmRNA水平；PPT基因的主要表达产物P物质通过非NK1受体增加BDNF基因表达,此作用受谷氨酸NMDA受体调节；PACAP引起细胞内PDYN mRNA及其活性蛋白产物dynorphin A表达增加,BDNF则抑制PDYN mRNA表达。进一步对PACAP诱导PDYN mRNA表达的作用机制进行探讨,发现PACAP对PDYN mRNA表达的诱导作用具有时间和剂量依赖性；PACAP增加PDYN mRNA表达作用强于肠血管活性多肽(Vasoactive intestinal polypeptide, VIP),提示PACAP主要通过PAC1受体引起PDYN mRNA表达增加：forsko lin可诱导PDYNmRNA表达,而PKC的激活剂TPA则未显示增加PDYN mRNA表达的作用,同时PKA抑制剂H89能完全阻断PACAP引起的PDYN mRNA表达增加,提示PACAP通过PAC1/PKA途径发挥对PDYN mRNA表达的影响；蛋白质合成抑制剂CHX进一步升高PACAP诱导的PDYN mRNA表达,提示PACAP直接引起PDYN mRNA表达而无需新蛋白质合成,PACAP诱导的蛋白质表达可能进一步抑制PDYN mRNA表达；NMDA受体拮抗剂APV可抑制PACAP诱导的BDNF, c-fos mRNA表达,但对PACAP诱导的PDYN mRNA表达无影响,提示NMDA受体不参与PACAP对PDYN mRNA表达的诱导作用。
本研究首次发现去极化与腺苷酸环化酶激活协同升高原代培养大鼠皮层神经元内PDYN、CCK、PPT mRNA表达,SP通过非NK1受体途径引起BDNF mRNA表达增加；首次发现PACAP主要由其特异性PAC1受体介导、通过PKA信号通路直接引起PDYN基因表达增加,提示PACAP是内源性PDYN基因表达上游调节物。鉴于PACAP与PDYN在中枢神经系统表达部位的一致性,以及两者都参与伤害性感受及精神障碍疾病的调节过程,PACAP诱导的PDYN基因表达可能参与上述疾病过程,本文的研究结果为进一步探索相关疾病发生及治疗提供一定的理论基础。
Pituitary adenylate cyclase-activating polypeptide (PACAP) was found to be synergistically increased by calcium influx and increased content of cAMP in neurons, and is involved in the regulation of synaptic plasticity and thereby related to the control of emotion and other central nervous system (CNS) function. Brain-derived neurotrophic factor (BDNF) expression is increased by PACAP in neurons, and plays an important role in neuronal survival, differentiation and synaptic plasticity. Proteins encoded by the genes of prodynorphin (PDYN), cholecystokinin (CCK), and preprotachykinin (PPT) are reported to be involved in variety of CNS function, and are likewise related to the development or pathology of affective disorders such as anxiety or depression. It was found that KC1and forskolin, an adenylate cyclase activator, synergistically increased PACAP mRNA expression, and increase BDNF gene expression in a non-synergistical manner. However, it is still unclear whether PACAP and BDNF, as endogenous regulators, interact with PDYN, CCK, and PPT gene. And if there is an interaction, how does it go? Therefore, the present study investigated genes expression induced by calcium influx and increased cAMP content in neurons, as well as interactions of PDYN, CCK, and PPT gene expression with PACAP or BDNF. And further study was done to investigate the underlying mechanism after our discovery of PACAP-induced PDYN expression.
Primary cultured rat cortical neurons were employed to investigate mRNA expressiooninduced by KC1and/or forskolin, which result in a calcium influx and increased content of cAMP, by techniques of genechip and quantitative RT-PCR. And further study on the effect and mechanism of PACAP-induced PDYN or BDNF mRNA expression was performed by immuno fluorescence and quantitative RT-PCR. It was found that KC1and forskolin synergistically upregulated mRNA expression of PDYN, CCK, and PPT in neurons. Substance P, the biological active product of PPT, increased the expression of BDNF mRNA via a non-NK1receptor mediated pathway. However, this effect is regulated by NMDA receptor. PDYN mRNA expression and its bioactive protein product, dynorphin A, were significantly increased by the treatment of PACAP, while PDYN mRNA expression was decreased by that of BDNF. a further study on the mechanism of PACAP-induced PDYN mRNA expression was performed. It was found that PACAP increased PDYN mRNA expression in a dose-and time-dependent manner. PACAP had much more of an effect than vasoactive intestinal polypeptide (VIP) on PDYN mRNA expression, suggesting a major role of PAC1receptor in PACAP-induced PDYN mRNA expression. PDYN mRNA expression was increased by forskolin, activator of adenylate cyclase, but not TPA, a potent activator of PKC. Meanwhile, the increase in PDYN mRNA expression induced by PACAP was completely inhibited by pretreatment with H89, an inhibitor of PKA, indicating that PACAP-induced Pdyn mRNA expression is dependent on a PACAP/PAC1/PKA pathway. Furthermore, it was found that PACAP-induced Pdyn mRNA expression was actually enhanced by cycloheximide (CHX), an inhibitor of-protein synthesis, indicating thatt de novo protein synthesis is not necessary for the PACAP-induced PDYN mRNA expression. The PACAP-induced BDNF and c-fos mRNA expression was inhibited by APV whereas the expression of PDYN mRNA induced by PACAP was not affected in the presence of APV, indicating no involvement of NMDA-R activation in the PACAP-induced Pdyn mRNA expression.
For the first time we found that depolarization and adenylate cyclase activation synergistically increase PDYN, CCK, and PPT mRNA expression in primary cultured rat cortical neurons; SP induced BDNF expression via a non-NK1receptor mediated, but NMDA receptor mediated pathway; PACAP directly induced PDYN mRNA expression via a PAC1/PKA mediated pathway, indicating that PACAP is an endogenous upstream regulator for inducing PDYN mRNA expression. Considering the distribution and biological activities of PACAP and dynorphins in CNS, it is highly possible that a cascade of PACAP-induced gene expression, including the expression of PDYN, could be involved in regulating not only nociception but also a variety of neuronal functions and diseases in the central nervous system.
本文采用KC1与腺苷酸环化酶激活剂forskolin共同作用于原代培养的大鼠皮层神经元,分别引起神经元去极化进而诱导Ca2+内流及细胞内cAMP信号增强,通过基因芯片技术、定量RT-PCR方法检测大鼠皮层神经元内PDYN基因、CCK基因及PPT基因的表达水平；并进一步采用定量RT-PCR及细胞免疫荧光技术研究了PACAP对PDYN、 BDNF等基因表达的影响与机制。
研究发现,KCl与forskolin升高包括PDYN、CCK、PPT基因在内的62种基因至其基础表达水平3倍以上；协同升高神经元内PDYN、CCK、PPTmRNA水平；PPT基因的主要表达产物P物质通过非NK1受体增加BDNF基因表达,此作用受谷氨酸NMDA受体调节；PACAP引起细胞内PDYN mRNA及其活性蛋白产物dynorphin A表达增加,BDNF则抑制PDYN mRNA表达。进一步对PACAP诱导PDYN mRNA表达的作用机制进行探讨,发现PACAP对PDYN mRNA表达的诱导作用具有时间和剂量依赖性；PACAP增加PDYN mRNA表达作用强于肠血管活性多肽(Vasoactive intestinal polypeptide, VIP),提示PACAP主要通过PAC1受体引起PDYN mRNA表达增加：forsko lin可诱导PDYNmRNA表达,而PKC的激活剂TPA则未显示增加PDYN mRNA表达的作用,同时PKA抑制剂H89能完全阻断PACAP引起的PDYN mRNA表达增加,提示PACAP通过PAC1/PKA途径发挥对PDYN mRNA表达的影响；蛋白质合成抑制剂CHX进一步升高PACAP诱导的PDYN mRNA表达,提示PACAP直接引起PDYN mRNA表达而无需新蛋白质合成,PACAP诱导的蛋白质表达可能进一步抑制PDYN mRNA表达；NMDA受体拮抗剂APV可抑制PACAP诱导的BDNF, c-fos mRNA表达,但对PACAP诱导的PDYN mRNA表达无影响,提示NMDA受体不参与PACAP对PDYN mRNA表达的诱导作用。
本研究首次发现去极化与腺苷酸环化酶激活协同升高原代培养大鼠皮层神经元内PDYN、CCK、PPT mRNA表达,SP通过非NK1受体途径引起BDNF mRNA表达增加；首次发现PACAP主要由其特异性PAC1受体介导、通过PKA信号通路直接引起PDYN基因表达增加,提示PACAP是内源性PDYN基因表达上游调节物。鉴于PACAP与PDYN在中枢神经系统表达部位的一致性,以及两者都参与伤害性感受及精神障碍疾病的调节过程,PACAP诱导的PDYN基因表达可能参与上述疾病过程,本文的研究结果为进一步探索相关疾病发生及治疗提供一定的理论基础。
Pituitary adenylate cyclase-activating polypeptide (PACAP) was found to be synergistically increased by calcium influx and increased content of cAMP in neurons, and is involved in the regulation of synaptic plasticity and thereby related to the control of emotion and other central nervous system (CNS) function. Brain-derived neurotrophic factor (BDNF) expression is increased by PACAP in neurons, and plays an important role in neuronal survival, differentiation and synaptic plasticity. Proteins encoded by the genes of prodynorphin (PDYN), cholecystokinin (CCK), and preprotachykinin (PPT) are reported to be involved in variety of CNS function, and are likewise related to the development or pathology of affective disorders such as anxiety or depression. It was found that KC1and forskolin, an adenylate cyclase activator, synergistically increased PACAP mRNA expression, and increase BDNF gene expression in a non-synergistical manner. However, it is still unclear whether PACAP and BDNF, as endogenous regulators, interact with PDYN, CCK, and PPT gene. And if there is an interaction, how does it go? Therefore, the present study investigated genes expression induced by calcium influx and increased cAMP content in neurons, as well as interactions of PDYN, CCK, and PPT gene expression with PACAP or BDNF. And further study was done to investigate the underlying mechanism after our discovery of PACAP-induced PDYN expression.
Primary cultured rat cortical neurons were employed to investigate mRNA expressiooninduced by KC1and/or forskolin, which result in a calcium influx and increased content of cAMP, by techniques of genechip and quantitative RT-PCR. And further study on the effect and mechanism of PACAP-induced PDYN or BDNF mRNA expression was performed by immuno fluorescence and quantitative RT-PCR. It was found that KC1and forskolin synergistically upregulated mRNA expression of PDYN, CCK, and PPT in neurons. Substance P, the biological active product of PPT, increased the expression of BDNF mRNA via a non-NK1receptor mediated pathway. However, this effect is regulated by NMDA receptor. PDYN mRNA expression and its bioactive protein product, dynorphin A, were significantly increased by the treatment of PACAP, while PDYN mRNA expression was decreased by that of BDNF. a further study on the mechanism of PACAP-induced PDYN mRNA expression was performed. It was found that PACAP increased PDYN mRNA expression in a dose-and time-dependent manner. PACAP had much more of an effect than vasoactive intestinal polypeptide (VIP) on PDYN mRNA expression, suggesting a major role of PAC1receptor in PACAP-induced PDYN mRNA expression. PDYN mRNA expression was increased by forskolin, activator of adenylate cyclase, but not TPA, a potent activator of PKC. Meanwhile, the increase in PDYN mRNA expression induced by PACAP was completely inhibited by pretreatment with H89, an inhibitor of PKA, indicating that PACAP-induced Pdyn mRNA expression is dependent on a PACAP/PAC1/PKA pathway. Furthermore, it was found that PACAP-induced Pdyn mRNA expression was actually enhanced by cycloheximide (CHX), an inhibitor of-protein synthesis, indicating thatt de novo protein synthesis is not necessary for the PACAP-induced PDYN mRNA expression. The PACAP-induced BDNF and c-fos mRNA expression was inhibited by APV whereas the expression of PDYN mRNA induced by PACAP was not affected in the presence of APV, indicating no involvement of NMDA-R activation in the PACAP-induced Pdyn mRNA expression.
For the first time we found that depolarization and adenylate cyclase activation synergistically increase PDYN, CCK, and PPT mRNA expression in primary cultured rat cortical neurons; SP induced BDNF expression via a non-NK1receptor mediated, but NMDA receptor mediated pathway; PACAP directly induced PDYN mRNA expression via a PAC1/PKA mediated pathway, indicating that PACAP is an endogenous upstream regulator for inducing PDYN mRNA expression. Considering the distribution and biological activities of PACAP and dynorphins in CNS, it is highly possible that a cascade of PACAP-induced gene expression, including the expression of PDYN, could be involved in regulating not only nociception but also a variety of neuronal functions and diseases in the central nervous system.
引文
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