MECHANISMS OF NEUROSECRETION

我们对突触传递机制的理解 是建立在神经肌肉信息的基础上的 交界处。过去40年的研究表明， 通过神经终末膜中的电压依赖性通道的内流 触发乙酰胆碱递质的释放释放事件 本身和乙酰胆碱的水解是快速的，限制了可用性 突触间隙中的传递物。l毫秒。因此，在本发明中， 突触传递的时间进程几乎完全由 突触后肌肉膜的特性。通过这些方式， 确保了协调运动所需的同步、快速信号。 所有的突触都是这样吗？你可能认为该 突触的生理功能决定了它的特性，导致 突触传递基础机制的变化。在 例如，中枢神经系统，几乎所有的突触 电位低于阈值，突触传递的速度可能 没有多个突触前输入的整合重要-- 由延长的而非短暂的突触后电位促进的过程。的确， 大量研究表明，中枢神经元中的突触电流 表现出一种持久的成分，这可能是由于高- 亲和力突触后受体结合或维持可用性 突触间隙中的神经递质我们已经开始剖析 突触前对突触传递时程的贡献 通过研究释放事件本身，使用 亚秒级分辨率的快速生化方法。我们的研究结果表明 与运动神经元释放乙酰胆碱相反， 从中枢神经末梢的释放延长，这表明， 突触间隙内递质的可用性可能在 控制突触传递的时间进程。我们还表明 负责谷氨酸释放的钙通道与 那些在神经肌肉连接处。初步迹象表明， 不同的释放机制之间存在根本差异， 中枢神经系统内的神经递质。我们提出了三 具体目标是研究这些机制。目标1将侧重于 描述时间进程和目标2识别钙通道 负责谷氨酸的释放目标3将比较释放 谷氨酸的性质与GABA、去甲肾上腺素和 多巴胺总的来说，这些研究的结果可能会 强调我们可以区分（和实验调节）的方法 中枢神经系统中不同递质的释放。在 从长远来看，这些信息可能对治疗有价值。 神经系统疾病的管理，如帕金森症和 精神分裂症--与特定功能障碍有关的疾病 神经递质系统

Our understanding of the mechanisms that underlie synaptic transmission has been built on a foundation of information from the nerve-muscle junction. Studies over the past 40 years have established that calcium influx through voltage-dependent channels in the nerve terminal membrane triggers release of the transmitter acetylcholine. The release event itself and hydrolysis of acetylcholine are fast, limiting the availability of transmitter in the synaptic cleft to ca. l millisecond. As a result, the time course for synaptic transmission is determined almost entirely by the properties of the postsynaptic, muscle membrane. In these ways, the synchonous, rapid signalling required for coordinated movement is insured. Is this the case for all synapses? One might imagine that the physiological function of a synapse dictates its properties, leading to variations in fundamental mechanisms underlying synaptic transmission. In the central nervous system, for example, where virtually all synaptic potentials are subthreshold, speed of synaptic transmission is likely to be less important than integration of multiple presynaptic inputs--a process promoted by prolonged, not brief, postsynaptic potentials. Indeed, a number of studies have shown that synaptic currents in central neurons exhibit a long-lasting component that could result either from high- affinity postsynaptic receptor binding or maintained availability of transmitter in the synaptic cleft. We have begun to dissect the presynaptic contribution to the time course for synaptic transmission in the central nervous system by studying the release event itself, using a rapid biochemical method with subsecond resolution. Our results argue that, in contrast to acetylcholine release from motoneurons, glutamate release from central nerve terminals is prolonged, suggesting that availability of transmitter within the synaptic cleft might play a role in controlling the time course of synaptic transmission. We have also shown that the calcium channels responsible for glutamate release differ from those at the nerve-muscle junction. Preliminary indications are that fundamental differences exist among the release mechanisms for different transmitters within the central nervous system as well. We propose three specific aims to investigate these mechanisms. Aim 1 will focus on describing the time course and Aim 2 on identifying the calcium channels responsible for glutamate release. Aim 3 will compare the release properties for glutamate with those for GABA, norepinephrine, and dopamine. Taken together, results from these studies are likely to highlight means by which we can discriminate (and experimentally regulate) release of different transmitters in the central nervous system. In the long term, such information might prove invaluable for therapeutic management of neurological disorders, such as Parkinsonism and schizophrenia--diseases that are associated with malfunctions in specific neurotransmitter systems.