ADENOSINE DERIVATIVES AND SYNAPTIC TRANSMISSION

腺苷衍生物和突触传递

• 批准号: 6393288
• 负责人: EUGENE M SILINSKY
• 金额: $ 38.09万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-05-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6393288
• 关键词: Anura; acetylcholine; adenosine; adenosine triphosphate; botulinum toxins; calcium flux; cell line; genetically modified animals; guinea pigs; laboratory mouse; membrane channels; molecular cloning; motor neurons; neural inhibition; neuromuscular junction; neuromuscular transmission; neurotoxins; neurotransmitter transport; nicotinic receptors; purinergic receptor

DESCRIPTION (Adapted from applicant's abstract) The overall objective of the proposed research is to further our knowledge of the molecular mechanisms by which adenosine derivatives affect the vertebrate nervous system. During this past period of support, we found that ATP is released together with the neurotransmitter acetylcholine (ACh) within milliseconds of a nerve impulse and, after hydrolysis to adenosine, is the physiological mediator of skeletal neuromuscular depression. We also found evidence for mutually-inhibitory interactions between nicotinic ACh receptors and P2X ATP receptors in adult mammalian neurons. During the next period of support, we will continue to study the behavior of adenosine derivatives as presynaptic inhibitors of ACh release and postsynaptic inhibitors of the action of ACh on nicotinic synapses. There are two specific aims underlying the overall objective as follows. For specific aim 1, we will attempt to determine the specific molecular mechanisms responsible for the inhibitory effect of adenosine on ACh release. Towards this aim, we will activate or interfere with specific target proteins in the nerve ending and examine if the effects of adenosine are altered. For specific aim 2, we will study the mechanisms underlying the inhibitory electrophysiological interactions between nicotinic ACh receptors and P2X ATP receptors on adult mammalian sympathetic neurons. Such interactions have been found to occur even with very low concentrations of ATP and nicotine. With regards to the significance of the proposed research, adenosine derivatives have been implicated as mediators of physiological and pathological activity in the vertebrate nervous system. The experiments at the neuromuscular junction demonstrate that endogenous adenosine is a physiological mediator of neuromuscular depression at frog and mammalian synapses. Determining the specific nerve terminal targets for the inhibitory actions of adenosine would thus provide both important basic science information and potential clinical benefits. For example, it is possible that selective adenosine receptor antagonists can be used to prevent the debilitating neuromuscular depression that occurs in patients with neuromuscular disorders such a myasthenia gravis. The results with ATP will provide valuable additional knowledge on the relationship between purinergic and nicotinic synapses in mammals. Indeed, fast excitatory purinergic transmission with similar properties to the neurons we study occurs in regions of the CNS associated with cholinergic synapses and with Alzheimer's disease.

描述（改编自申请人的摘要）该项目的总体目标 拟议的研究是为了进一步了解分子机制 哪些腺苷衍生物影响脊椎动物的神经系统。在此期间 过去一段时间的支持，我们发现ATP是与 神经冲动后几毫秒内产生神经递质乙酰胆碱 (ACh) 水解为腺苷后，是骨骼肌的生理介质 神经肌肉抑郁症。我们还发现了相互抑制的证据 成人烟碱型 ACh 受体与 P2X ATP 受体之间的相互作用 哺乳动物神经元。在接下来的支持期间，我们将继续研究 腺苷衍生物作为乙酰胆碱释放的突触前抑制剂的行为 和乙酰胆碱对烟碱突触作用的突触后抑制剂。那里 总体目标背后有两个具体目标，如下所示。对于具体的 目标1，我们将尝试确定具体的分子机制 负责腺苷对乙酰胆碱释放的抑制作用。朝这个方向 目标，我们将激活或干扰神经中的特定目标蛋白 结束并检查腺苷的作用是否改变。对于具体目标 2， 我们将研究抑制性电生理学的潜在机制 成人烟碱型 ACh 受体与 P2X ATP 受体之间的相互作用 哺乳动物交感神经元。人们发现这种相互作用甚至会发生 ATP 和尼古丁浓度非常低。 关于拟议研究的意义，腺苷 衍生物被认为是生理和病理的介质 脊椎动物神经系统的活动。神经肌肉实验 连接证明内源性腺苷是 青蛙和哺乳动物突触的神经肌肉抑制。确定 腺苷抑制作用的特定神经末梢靶点 从而提供重要的基础科学信息和潜在的临床信息 好处。例如，选择性腺苷受体可能 拮抗剂可用于预防使人衰弱的神经肌肉抑郁症 发生在患有重症肌无力等神经肌肉疾病的患者中。 ATP 的结果将提供有关以下方面的宝贵的额外知识： 哺乳动物嘌呤能和烟碱突触之间的关系。确实，快 兴奋性嘌呤能传递与我们的神经元具有相似的特性 研究发生在与胆碱能突触相关的中枢神经系统区域 患有阿尔茨海默病。