MECHANISMS OF NEUROSECRETION

我们对突触传递机制的理解 建立在来自神经肌肉的信息的基础上 交叉口。过去40年的研究已经证实，钙 通过神经末梢膜上的电压依赖通道内流 触发递质乙酰胆碱的释放。发布活动 乙酰胆碱本身和乙酰胆碱的水解速度很快，限制了其可用性 突触间隙中的递质约为L毫秒。结果, 突触传递的时间进程几乎完全由 突触后肌膜的特性。通过这些方式， 协调移动所需的同步、快速信号是有保障的。 所有的突触都是这样吗？有人可能会想象， 突触的生理功能决定了它的特性，导致 突触传递的基本机制的变化。在……里面 例如，中枢神经系统，在那里几乎所有的突触 电位是亚阈值，突触传递的速度很可能 不如整合多个突触前输入那么重要--a 突触后电位是由长时间的，而不是短暂的，促进的。的确， 大量研究表明，中枢神经元中的突触电流 展示了一种持久的成分，这可能是由于高- 亲和力突触后受体结合或维持的可用性 突触间隙中的传递器。我们已经开始剖析 突触前在突触传递时程中的作用 通过研究释放事件本身，使用 亚秒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，谷氨酸 中枢神经末梢的释放时间延长，表明 突触间隙内递质的可获得性可能在 控制突触传递的时间进程。我们还展示了 负责谷氨酸释放的钙通道与 那些在神经肌肉交界处的。初步迹象表明， 不同的释放机制之间存在根本的差异 中枢神经系统内的传输器也是如此。我们提出三个建议 具体目的是研究这些机制。目标1将专注于 描述识别钙通道的时间过程和目标2 负责谷氨酸的释放。Aim 3将比较这一版本 谷氨酸的性质与GABA、去甲肾上腺素和 多巴胺。总而言之，这些研究的结果可能会 突出我们可以区别对待(和实验性监管)的方法 中枢神经系统释放不同的递质。在 从长远来看，这样的信息可能被证明是无价的治疗 神经疾病的管理，如帕金森氏症和 精神分裂症--与特定功能障碍相关的疾病 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.