ADENOSINE DERIVATIVES AND SYNAPTIC TRANSMISSION

描述(改编自申请人的摘要) 建议的研究是通过以下方式加深我们对分子机制的了解 哪些腺苷衍生物会影响脊椎动物的神经系统。在此期间 在过去的支持期内，我们发现ATP与 神经冲动毫秒内的神经递质乙酰胆碱(ACh) 并且，在水解为腺苷之后，是骨骼的生理媒介 神经肌肉抑郁。我们还发现了相互抑制的证据 成人烟碱型ACh受体与P2X-ATP受体的相互作用 哺乳动物的神经元。在接下来的支持期内，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 以及突触后抑制ACh对尼古丁突触的作用。那里 总目标的基础是两个具体目标，具体如下。对于特定的 目的1，我们将尝试确定特定的分子机制 腺苷对ACh释放的抑制作用。朝向这个方向 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发生改变。对于特定的目标2， 我们将研究抑制电生理的机制。 烟碱型ACh受体与P2X-ATP受体在成人中的相互作用 哺乳动物的交感神经元。这种相互作用已经被发现甚至发生在 三磷酸腺苷和尼古丁的浓度非常低。 关于拟议研究的意义，腺苷 衍生物被认为是生理和病理过程中的介质。 脊椎动物神经系统的活动。在神经肌肉中心的实验 连接研究表明内源性腺苷是一种生理调节因子 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应用 福利。例如，选择性腺苷受体有可能 拮抗剂可以用来预防衰弱的神经肌肉抑制。 这种情况会发生在患有神经肌肉疾病的患者身上，比如重症肌无力。 对ATP的研究结果将提供有关 哺乳动物中嘌呤能突触与烟碱能突触的关系。的确，很快 兴奋性嘌呤能传递具有与WE神经元相似的性质 研究发生在中枢神经系统与胆碱能突触和 患有阿尔茨海默氏症。

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.