PURINERGIC NEUROGENIC MUCOSAL SECRETION

描述(申请人提供)：这个项目的总体目标是描述一种新的由肠道神经系统中的代谢性ATP受体(P2Y1受体)介导的嘌呤能慢兴奋性突触后电位(EPSP)。在初步研究中，P2Y1受体拮抗剂MRS2179选择性地阻断了粘膜下神经元中由ATP引起的慢EPSP和慢EPSP样反应，从而证明了嘌呤能慢反应EPSP的存在。粘膜下分泌运动神经元中的嘌呤能慢EPSP是由ATP和P2Y1受体的突触释放所介导的假说将在形态鉴定的神经元中得到药理学检验。分子克隆和功能表达将被用来更好地描述P2Y1受体的特征。这一建议来自试点/可行性结果，该结果表明，肠分泌运动神经元接受来自肌间神经丛神经元、粘膜下神经丛邻近神经元和椎前神经节交感神经元的嘌呤能慢兴奋性突触输入。在Ussing小室实验中，选择性的P2Y1受体拮抗剂MRS2179抑制了由应用ATP和跨壁电刺激分泌运动神经元引起的神经源性分泌反应，这一发现增加了对这一假说的支持。实现这一提议的目的将使人们更好地理解新发现的嘌呤能慢速EPSP在细胞、分子和整合系统水平上在肠道神经系统中的作用。试点/可行性数据首次证明了肠道神经系统中存在一种具有功能的嘌呤能慢速EPSP。P2Y1受体介导肠道分泌运动神经元中缓慢的EPSP，这一发现可能有助于开发治疗肠易激综合征、炎症性肠病和其他排便障碍的新药，靶向于控制肠道分泌的肠神经元池中的P2Y1受体或ATP代谢通路。

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.