ROLE OF GALANIN RECEPTORS IN GASTROINTESTINAL MOTILITY

甘丙肽受体在胃肠动力中的作用

• 批准号: 7226052
• 负责人: CATIA STERNINI
• 金额: $ 13.91万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2008-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7226052
• 关键词: central neural pathway /tract; confocal scanning microscopy; galanin; gastrointestinal motility /pressure; guinea pigs; immunocytochemistry; in situ hybridization; laboratory rat; neuropeptide receptor; neurotransmitter transport; protein localization; receptor expression; western blottings

Galanin exerts excitatory and inhibitory effects on gastrointestinal motility either directly by acting on the muscle or indirectly by acting on neuronal pathways. Galanin actions are mediated by three subtypes of galanin receptors (GAL-R), GAL- R1, GAL-R2 and GAL-R3, which are G protein-coupled receptors with distinct pharmacological profiles that utilize different intracellular signaling pathways. These observations strongly suggest that different galanin receptors mediate the different actions of galanin on gastrointestinal functions, including motility. The neurally-mediated inhibitory actions of galanin on gastrointestinal motility and the galanin receptor subtypes involved in this inhibitory modulation by galanin are the focus of this proposal. The hypothesis to be tested is that GAL-R1 and GAL-R3 mediate the indirect inhibitory effect of galanin on gastrointestinal motility primarily through the inhibition of transmitter release from excitatory pathways, and that GAL-R2 stimulates the inhibitory pathway by inducing inhibitory transmitter release. These studies will utilize the rat and guinea pig as model systems and will combine morphological and functional approaches including in vitro and in vivo studies. Specific aim 1 will a) elucidate the cellular localization of GAL-Rs in the gastrointestinal tract of the rat and guinea pig, and b) identify the neuronal pathways expressing these receptors. Specific aim 2 will characterize the role of GAL-Rs on galanin inhibition of neurogenic transmission using the muscle-myenteric plexus preparations of the guinea pig ileum in vitro. These studies will a) evaluate whether GAL-R1 and GAL-R3 mediate the inhibitory effect of galanin on neurotransmission by determining the diminution of electrically-stimulated muscle twitch and the reduction of acetylcholine release, and b) investigate whether GAL-R2 activation induces a neurally-mediated inhibitory response. Specific aim 3 will investigate the role of galanin and GAL-Rs on the ascending excitatory reflex and peristalsis in the guinea pig ileum in vitro by determining a) the effects of galanin on physiological parameters Of peristalsis, b) the sites of action of galanin on peristaltic reflex, c) which GAL-Rs are involved and d) whether galanin is released during peristalsis. Specific aim 4 will investigate the role of GAL-R activation in the inhibition of gastrointestinal motility and transit in vivo in the rat. These studies will provide insights into the role and site of action of galanin and its receptors in modulating gastrointestinal motility and the basis for better understanding pathways involved in gastrointestinal dysmotility.

甘丙肽通过直接作用于肌肉或间接作用于神经元通路对胃肠运动产生兴奋和抑制作用。甘丙氨酸的作用由三种亚型的甘丙氨酸受体（GAL- r）、GAL- R1、GAL- r2和GAL- r3介导，它们是具有不同药理特征的G蛋白偶联受体，利用不同的细胞内信号通路。这些观察结果强烈表明，不同的丙氨酸受体介导丙氨酸对胃肠功能的不同作用，包括胃肠运动。神经介导的甘丙肽对胃肠运动的抑制作用和参与这种抑制调节的甘丙肽受体亚型是本提案的重点。待验证的假设是GAL-R1和GAL-R3主要通过抑制兴奋性通路的递质释放介导甘丙肽对胃肠运动的间接抑制作用，GAL-R2通过诱导抑制性递质释放刺激抑制通路。这些研究将利用大鼠和豚鼠作为模型系统，并结合形态学和功能方法，包括体外和体内研究。具体目的1将a)阐明GAL-Rs在大鼠和豚鼠胃肠道中的细胞定位，b)确定表达这些受体的神经元通路。特异性目的2将描述GAL-Rs在体外豚鼠回肠肌-肌丛制剂中对甘丙肽抑制神经源性传递的作用。这些研究将a)通过测定电刺激肌肉抽搐的减少和乙酰胆碱释放的减少来评估GAL-R1和GAL-R3是否介导了甘丙氨酸对神经传递的抑制作用；b)研究GAL-R2的激活是否诱导了神经介导的抑制反应。具体目的3将探讨甘丙肽和GAL-Rs对豚鼠离体回肠上升兴奋反射和蠕动的作用，通过确定a)甘丙肽对蠕动生理参数的影响，b)甘丙肽对蠕动反射的作用部位，c)甘丙肽参与哪些GAL-Rs， d)甘丙肽在蠕动过程中是否释放。特异性目的4将探讨GAL-R激活在抑制大鼠体内胃肠运动和转运中的作用。这些研究将深入了解甘丙肽及其受体在调节胃肠运动中的作用和作用部位，并为更好地理解胃肠运动障碍的途径奠定基础。