Control of Neurohormone Release at Nerve Endings

神经细胞之间的交流最终依赖于一个神经细胞释放被称为神经递质的化学信使，以及随后释放的神经递质激活另一个神经细胞。神经递质从神经细胞中称为神经末梢或神经末梢的特殊部分释放出来。神经末梢释放神经递质最重要的起始者是神经末梢内游离钙的浓度。由于它们的体积很小，并且与完整组织中的神经胶质细胞和其他神经细胞区域混合在一起，因此对脊椎动物神经末梢的基本分泌机制的直接研究一直受到限制。这项建议的目的是利用一种独特的脊椎动物神经末梢制剂来表征钙与诱导化学信使分泌之间的基本关系。在拟议的研究中，将使用提供高定量和高时间分辨率的最先进的电生理和光学方法。将解决的具体问题包括：细胞内钙变化的性质对启动分泌最重要的是什么？哪些钙进入途径对分泌反应的诱导最为重要？电活动的持续激活是否改变了这些流入途径的重要性？此外，一些特定的蛋白质最近被生化证据牵连到导致分泌的一连串事件中。到目前为止，这些蛋白质的具体功能还没有被阐明，这是本提案的一个具体目的。

The communication between nerve cells ultimately depends on release of chemical messengers termed neurotransmitters from one nerve cell and subsequent activation of another nerve cell by the released neurotransmitter. Neurotransmitters are released from a specialized portions of a nerve cell called nerve endings or nerve terminals. The most important initiator of neurotransmitter release at nerve terminals is the concentration of free calcium within the terminal. As a consequence of their small size and of their being mixed with glial cells and other nerve cell regions in intact tissue, direct investigation of the basic secretory mechanisms at nerve endings of vertebrates has been limited. It is the purpose of this proposal to utilize a unique nerve terminal preparations of vertebrates which overcomes the above limitations to characterize the fundamental relationships between calcium and induction of secretion of the chemical messengers. State of the art electrophysiological and optical approaches which provide high quantitative and high time resolution will be used in the proposed studies. Specific questions that will be addressed include: What are the qualities of the changes in intracellular calcium that are most important for initiation of secretion? Which calcium entry pathways are most important for induction of the secretory response? Does continued activation by electrical activity alter the importance of these influx pathways? In addition, a number of specific proteins have recently been implicated in the chain of events leading to secretion by biochemical evidence. To date, the specific functions of these proteins have not been elucidated and is a specific aim of this proposal.