ROLE OF GALANIN RECEPTORS IN GASTROINTESTINAL MOTILITY

甘丙肽受体在胃肠动力中的作用

• 批准号: 6197837
• 负责人: CATIA STERNINI
• 金额: $ 22.78万
• 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 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6197837
• 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.

甘丙素通过直接作用于肌肉或间接作用于神经通路，对胃肠运动产生兴奋和抑制作用。甘丙肽的作用由甘丙肽受体的三种亚型GAL-R、GAL-R2和GAL-R3介导，它们是G蛋白偶联受体，具有不同的药理特征，利用不同的细胞内信号转导途径。这些观察有力地表明，不同的甘丙素受体介导甘丙肽对胃肠功能的不同作用，包括运动。甘丙肽对胃肠运动的神经介导的抑制作用以及甘丙肽参与这一抑制调节的甘丙素受体亚型是本研究的重点。需要检验的假设是，Gal-R1和Gal-R3主要通过抑制兴奋通路的递质释放来间接抑制甘丙肽对胃肠运动的抑制作用，而Gal-R2则通过诱导抑制性递质释放来刺激抑制通路。这些研究将利用大鼠和豚鼠作为模型系统，并将结合形态和功能方法，包括体外和体内研究。具体目的1)阐明Gal-Rs在大鼠和豚鼠胃肠道的细胞定位，以及b)确定表达这些受体的神经元通路。具体目的2利用豚鼠回肠肌间神经丛制剂，研究Gal-Rs在甘丙素抑制神经源性传递中的作用。这些研究将a)通过测定电刺激的肌肉痉挛的减少和乙酰胆碱释放的减少来评估Gal-R1和Gal-R3是否介导甘丙素对神经传递的抑制作用，以及b)研究Gal-R2激活是否诱导神经介导的抑制反应。具体目标3将通过确定a)甘丙素对豚鼠回肠蠕动生理参数的影响，b)甘丙素在蠕动反射中的作用部位，c)参与哪些Gal-R，d)甘丙素在蠕动过程中是否释放，来研究甘丙素及其受体在豚鼠回肠上行兴奋反射和蠕动中的作用。目的4探讨GAL-R激活在抑制大鼠体内胃肠运动和转运中的作用。这些研究将对甘丙肽及其受体在调节胃肠运动中的作用和作用部位提供深入的见解，并为更好地了解涉及胃肠运动障碍的通路奠定基础。