PRESYNAPTIC MECHANISMS IN THE INTESTINE

肠道中的突触前机制

• 批准号: 6381717
• 负责人: James J. Galligan
• 金额: $ 18.5万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 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 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6381717
• 关键词: acetylcholine; action potentials; adenosine triphosphate; electrophysiology; gastrointestinal motility /pressure; guinea pigs; membrane potentials; myenteric plexus; neural transmission; neuropeptide receptor; neuroregulation; neurotransmitter receptor; nicotinic receptors; purinergic receptor; receptor sensitivity; serotonin; serotonin receptor; substance P; tissue /cell culture

Presynaptic mechanisms are an important means for neurotransmitters, hormones, paracrine substances and drugs to modulate the activity of myenteric nerves and gut motility. Despite the clear importance of presynaptic mechanisms in regulating neurotransmission in the myenteric plexus, little is known about the details of these mechanisms. The proposed studies are designed to characterize these mechanisms. Electrophysiological methods will be used to study excitatory synaptic transmission between myenteric neurons in acutely isolated preparations of guinea pig intestine and between guinea pig myenteric neurons maintained under tissue culture conditions. These studies will investigate the contributions of acetylcholine (ACh) acting at nicotinic cholinergic receptors and ATP acting at P2X purine receptors, to fast excitatory synaptic potentials (fEPSPs) during long trains of stimulation. As nicotinic receptors desensitize quickly, it is anticipated that ACh will be the predominate transmitter early while ATP will predominate later in the train of activity. Presynaptic mechanisms controlling the release of these two important transmitters will also be investigated. These studies will focus on channels which provide the calcium needed for transmitter release and the presynaptic receptors which facilitate their release. The facilitatory effects of 5-HT4 receptor activation on fEPSPs mediated by ACh and ATP will be investigated. In addition, these studies will investigate the contribution of 5-HT3 and 5-HT4 receptors to excitation of enteric sensory nerve terminals. The role of presynaptic nicotinic acetylcholine receptors (nAChRs) in controlling the release of the slow synaptic transmitters, substance P/neurokinin A will also be investigated. These latter studies will attempt to establish that there are presynaptic nAChRs on the terminals of sensory neurons and that ACh released from sensory neurons facilitates SP/NKA release and enhances slow excitatory synaptic transmission. There are many disorders of gut motility which have their basis either directly or indirectly in alterations in enteric neurotransmission. These disorders include gastroesophageal reflux disease, the irritable bowel syndrome and chronic intestinal pseudo-obstruction. It is anticipated that these studies will provide new insights into mechanisms of synaptic transmission in the gut which could lead to the development of new and effect drug treatments for motility disorders.

突触前机制是神经递质，激素，旁分泌物质和药物的重要手段，可调节肌植血神经和肠运动的活性。尽管突触前机制在调节肌植物中的神经传递方面显而易见，但对这些机制的细节知之甚少。 拟议的研究旨在表征这些机制。电生理方法将用于研究肌肉神经元之间在急性分离的豚鼠肠系统中以及在组织培养条件下维持的豚鼠肌植物神经元之间的兴奋性突触传播。这些研究将研究作用于烟碱胆碱能受体和P2X嘌呤受体作用的乙酰胆碱（ACH）对在长期刺激期间快速兴奋性突触势（FEPSP）的贡献。 随着烟碱受体迅速脱敏，预计ACH将是较早的发射器，而ATP将在较晚的活动列车中占主导地位。 还将研究控制这两个重要发射机释放的突触前机制。 这些研究将集中于提供释放发射机所需的钙和促进其释放的突触前受体所需的钙。 将研究5-HT4受体激活对ACH和ATP介导的FEPSP的促进作用。 此外，这些研究将研究5-HT3和5-HT4受体对肠感觉神经末端激发的贡献。 突触前烟碱乙酰胆碱受体（NACHRS）在控制慢速突触发射器释放中的作用，还将研究物质P/Neurokinin a。 这些后者的研究将试图确定感觉神经元末端的突触前NACHR，而从感觉神经元释放的ACH促进了SP/NKA释放，并增强了缓慢的兴奋性突触传播。 肠运动的疾病有许多疾病，它们在肠道神经传递的改变中具有直接或间接的基础。 这些疾病包括胃食管反流疾病，肠易激综合征和慢性肠道伪腹结构。 可以预料，这些研究将为肠道中突触传播机制提供新的见解，这可能导致运动障碍的新和有效药物治疗。