ROLE OF GALANIN RECEPTORS IN GASTROINTESTINAL MOTILITY

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发挥兴奋和抑制作用。 甘丙肽作用由甘丙肽受体（GAL-R）的三种亚型GAL-R1、GAL-R2和GAL-R3介导，其是具有利用不同细胞内信号传导途径的不同药理学特征的G蛋白偶联受体。 这些观察结果强烈表明，不同的甘丙肽受体介导的不同的行动，甘丙肽对胃肠道功能，包括运动。 甘丙肽对胃肠动力的神经介导的抑制作用和甘丙肽参与这种抑制性调制的受体亚型是本建议的重点。 待检验的假设是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动力的间接抑制作用，GAL-R2通过诱导抑制性递质释放刺激抑制性通路。 这些研究将利用大鼠和豚鼠作为模型系统，并将结合联合收割机形态学和功能方法，包括体外和体内研究。具体目标1将a）阐明GAL-R在大鼠和豚鼠胃肠道中的细胞定位，和B）鉴定表达这些受体的神经元途径。具体目标2将在体外使用豚鼠回肠的肌间神经丛制备物表征GAL-Rs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是否介导甘丙肽对神经传递的抑制作用，和B）研究GAL-R2活化是否诱导神经介导的抑制反应。 具体目标3将通过确定a）甘丙肽对蠕动生理参数的影响，B）甘丙肽对蠕动反射的作用位点，c）哪些GAL-Rs参与，以及d）甘丙肽是否在蠕动期间释放，来研究甘丙肽和GAL-Rs对豚鼠回肠中的上行兴奋性反射和蠕动的作用。具体目标4将研究GAL-R激活在大鼠体内抑制胃肠运动和转运中的作用。 这些研究将提供深入了解甘丙肽及其受体在调节胃肠动力中的作用和作用部位，并为更好地了解胃肠动力障碍相关途径奠定基础。

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.