PURINERGIC NEUROGENIC MUCOSAL SECRETION

描述（由申请人提供）：本项目的总体目的是表征肠神经系统中由代谢型ATP受体（P2 Y1受体）介导的新型嘌呤能慢兴奋性突触后电位（EPSP）。 P2 Y1受体拮抗剂MRS 2179选择性地阻断粘膜下神经元ATP引起的慢EPSP和慢EPSP样反应。 嘌呤能慢EPSP由粘膜下分泌运动神经元中ATP和P2 Y1受体的突触释放介导的假设将在形态学鉴定的神经元中进行验证。 分子克隆和功能表达将用于更好地表征P2 Y1受体。 该建议出现在试点/可行性的结果，这表明假设肠分泌运动神经元接收嘌呤能慢兴奋性突触输入的神经元在肌间神经丛，从邻近的神经元在粘膜下神经丛和交感神经元在椎前神经节。 该假说的额外支持来自于以下发现：选择性P2 Y1受体拮抗剂MRS 2179抑制由应用ATP和在Ussing室实验中由分泌运动神经元的透壁电刺激引起的神经源性分泌反应。 实现这一建议的目的将导致更好地了解新发现的嘌呤能慢EPSP在肠神经系统中的作用在细胞，分子和集成系统水平。 试点/可行性数据是第一个证明在肠神经系统的功能性嘌呤能慢EPSP。 P2 Y1受体介导肠分泌运动神经元中的慢EPSP的发现可能有助于通过靶向控制肠分泌的肠神经元池中的P2 Y1受体或ATP代谢途径来开发用于治疗肠易激综合征、炎症性肠病和其他排便障碍的新药。

DESCRIPTION (provided by applicant): The overall aim of this project is to characterize a novel purinergic slow excitatory postsynaptic potential (EPSP) that is mediated by a metabotropic ATP receptor (P2Y1 receptor) in the enteric nervous system. Evidence for the existence of the purinergic slows EPSP emerged from pilot studies in which the P2Y1 receptor antagonist MRS2179 selectively blocked both the slow EPSP and slow EPSP-like responses evoked by ATP in submucosal neurons. The hypothesis that the purinergic slow EPSP is mediated by synaptic release of ATP and P2Y1 receptors in submucosal secretomotor neurons will be tested pharmacologically in morphologically identified neurons. Molecular cloning and functional expression will be used to better characterize the P2Y1 receptor. The proposal emerged from pilot/feasibility results, which suggest the hypothesis that intestinal secretomotor neurons receive purinergic slow excitatory synaptic input from neurons in the myenteric plexus, from neighboring neurons in the submucosal plexus and from sympathetic neurons in prevertebral ganglia. Added support for the hypothesis came from the discovery that the selective P2Y1 receptor antagonist MRS2179 suppressed neurogenic secretory responses evoked by application of ATP and by transmural electrical stimulation of secretomotor neurons in Ussing chamber experiments. Fulfilling the aims of this proposal will lead to better understanding of the role of a newly discovered purinergic slow EPSP in the enteric nervous system at the cellular, molecular and integrated system levels. The pilot/feasibility data are the first to demonstrate a functional purinergic slow EPSP in the enteric nervous system. The discovery that a P2Y1 receptor mediates the slow EPSP in intestinal secretomotor neurons might help in development of new drugs for treatment of the irritable bowel syndrome, inflammatory bowel disease and other disorders of defecation by targeting the P2Y1 receptor or ATP metabolic pathways in the pool of enteric neurons that control intestinal secretion.