ADENOSINE DERIVATIVES AND SYNAPTIC TRANSMISSION

描述：(改编自申请者摘要)总体目标 这项拟议的研究的目的是加深我们对 脊椎动物突触的腺苷衍生物。在前一笔拨款中 在此期间，申请人发现内源性腺苷，显然 来源于神经释放的三磷酸腺苷，可能是神经肌肉的原因 青蛙的抑郁。申请人还发现，通过一个 对结合了离子通道的受体的作用是一种快速兴奋 培养的哺乳动物神经元之间的神经递质。在接下来的几天里 支持期内，申请者将使用电生理方法 朝向以下三个具体目标：1)进一步研究 三磷酸腺苷来源的内源性腺苷可能是介体 通过测定量子三磷酸腺苷对青蛙神经肌肉抑制的影响 可与量子乙酰胆碱(ACh)一起检测释放 放手。申请者将使用由外向外的贴片。 分离的腹神经节神经元来进行这些实验。 这些贴片同时含有三磷酸腺苷和乙酰胆碱受体。他们的结果来自 过去的支持期表明，腺苷抑制ACh的释放 在青蛙中通过降低钙离子对战略的表观亲和力 分泌器的部件。这种影响是由一种 抑制肌醇磷脂的代谢，正如其他人所建议的那样？ 2)申请者将研究腺苷 衍生物抑制哺乳动物运动神经末梢的ACh释放和 它的生理重要性。三磷酸腺苷是神经肌肉的介质吗？ 小鼠运动神经末梢的抑制，如果是这样，是什么 机械装置？钙电流是否减少和/或是 细胞内钙离子促进ACh释放受损？是减少了 环磷酸腺苷浓度是抑制作用的中介因子 之前？3)特定目标3将进一步研究ATP的作用，如 一种快速的兴奋性发射机。建议进行的实验 神经肌肉连接几乎可以立即导致临床 关联性。具体地说，如果内源性腺苷是 哺乳动物中的神经肌肉抑制，那么就有可能 腺苷受体拮抗剂可以用来防止衰弱 重症肌无力患者出现的神经肌肉抑制。 ATP的结果还将提供关于以下方面的有价值的附加知识 嘌呤能突触的基本生理特性及其作用 哺乳动物与烟碱型突触的关系。

DESCRIPTION: (adapted from Applicant's Abstract) The overall objective of the proposed research is to further our knowledge of the importance of adenosine derivatives at vertebrate synapses. In the preceding grant period, the applicants found that endogenous adenosine, apparently derived from neurally-released ATP, may be the cause of neuromuscular depression in the frog. The applicants also found that ATP, via an action on receptors that incorporate ion channels, is a fast excitatory neurotransmitter between mammalian neurons in culture. In the ensuing period of support, the applicants will use electrophysiological methods towards the following three specific aims: 1) to study further the possibility that endogenous adenosine derived from ATP is the mediator of neuromuscular depression in the frog by determining if quantal ATP release can be detected in conjunction with quantal acetylcholine (ACh) release. The applicants will use outside-out patches from acutely dissociated neurons in celiac ganglion to perform these experiments. These patches contain both ATP and ACh receptors. Their results from this past period of support suggest that adenosine inhibits ACh release in frog by reducing the apparent affinity of Ca2+ for a strategic component of the secretory apparatus. Is this effect mediated by an inhibition of phosphoinositide turnover, as has been suggested by others? 2) The applicants will examine the mechanism by which adenosine derivatives inhibit ACh release from mammalian motor nerve endings and its physiological importance. Is ATP the mediator of neuromuscular depression at mouse motor nerve endings and if so, what is the mechanism? Are Ca2+ currents reduced and/or is the ability of intracellular Ca2+ to promote ACh release impaired? Is a decrease in cyclic AMP concentration the mediator of inhibition as suggested previously? 3) Specific Aim 3 will study further the action of ATP as a fast excitatory transmitter. The proposed experiments on neuromuscular junctions could result in almost immediate clinical relevance. Specifically, if endogenous adenosine is the mediator of neuromuscular depression in mammalian species, then it is possible that adenosine receptor antagonists can be used to prevent the debilitating neuromuscular depression that occurs in patients with myasthenia gravis. The results with ATP will also provide valuable additional knowledge on the basic physiological properties of purinergic synapses and their relationship to nicotinic synapses in mammals.