ADENOSINE DERIVATIVES AND SYNAPTIC TRANSMISSION

描述（改编自申请人的摘要） 拟议的研究是通过以下方式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 在过去的一段时间里，我们发现ATP是与 神经递质乙酰胆碱（ACh）在神经冲动的毫秒内 并且在水解为腺苷后，是骨骼肌的生理介质。 神经肌肉抑制我们还发现了相互抑制的证据 成人烟碱型ACh受体与P2 X-ATP受体的相互作用 哺乳动物神经元在接下来的支持期间，我们将继续研究 腺苷衍生物作为突触前ACh释放抑制剂的行为 和乙酰胆碱对烟碱突触作用的突触后抑制剂。那里 这两个具体目标构成了总体目标的基础，具体如下。为特定 目的1，我们将试图确定具体的分子机制 负责腺苷对ACh释放的抑制作用。为实现这一 目的，我们将激活或干扰神经中的特定靶蛋白 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的潜在机制， 成年大鼠脑内烟碱型ACh受体与P2 X-ATP受体的相互作用 哺乳动物的交感神经元已经发现这种相互作用甚至发生在 ATP和尼古丁的浓度很低 关于拟议研究的意义，腺苷 衍生物已被牵连作为介质的生理和病理 脊椎动物神经系统的活动。神经肌肉实验 连接表明内源性腺苷是 在青蛙和哺乳动物的突触上的神经肌肉抑制。确定 腺苷抑制作用的特定神经末梢靶点将 从而提供重要的基础科学信息和潜在的临床 效益例如，有可能选择性腺苷受体 拮抗剂可用于预防衰弱性神经肌肉抑制 这发生在患有神经肌肉疾病的患者身上，比如重症肌无力。 ATP的结果将提供有关 哺乳动物嘌呤能突触和烟碱能突触之间的关系。的确，快 兴奋性嘌呤能传递与神经元类似的性质，我们 研究发生在与胆碱能突触相关的CNS区域， 患有老年痴呆症

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.