GLUTAMATE-GATED CHANNELS IN CENTRAL/PERIPHERAL NEURONS

谷氨酸门控离子通道在细胞周期中发挥着重要作用。 神经系统。众所周知，它们可以调节细胞的去极化。 突触后神经元位于快速兴奋性突触，并被认为 调节某些细胞突触前终末的递质释放 类型。此外，它们还与神经细胞死亡有关。 与缺氧和过度兴奋有关。尽管已经有了很多 在过去的10年里了解了谷氨酸受体，许多方面 人们对它们的功能仍知之甚少。 拟议研究的长期目标是提供更好的 通过表征兴奋性突触传递来理解兴奋性突触传递 谷氨酸激活的受体和通道的运作。一个 第二个主要目标是发现可能允许 用于临床干预，以防止兴奋性毒性细胞死亡。膜片钳 将使用技术来记录全小区和单通道 兴奋性氨基酸在神经元中诱发的电流 原代细胞培养和新鲜分离的外周细胞 感觉神经节或来自中枢神经系统。 这项工作涉及两个主要项目。第一组实验将 检验一种假设，即金属表面的负电荷 中枢神经元中的N-甲基-D-天冬氨酸(NMDA)受体参与其 独特的浇注和渗透性能，包括调节 通道由甘氨酸、锌、多胺、质子、镁和地佐西平组成。这个 第二个项目侧重于非NMDA的激活和脱敏 中枢神经系统神经元和背根神经节神经元中的受体 表达这种受体的一种新形式。其具体目标是确定 脱敏通过研究脱敏作用的机理 已知可以改变门控的离子、药物和蛋白质的作用 非NMDA受体通道的行为。这是另一个主要关注点 项目是表征DRG表达的受体的药理学 神经元的目标是找到选择性的药物来区分 在受体的中枢和外周形式之间。这样的代理人 将是建立DRG受体功能的关键；它们 也可能被证明有能力控制疼痛的感觉，因为 这种受体在DRG中的表达似乎仅限于 伤害性神经元。

Glutamate-gated ion channels play a number of important roles in the nervous system. They are known to mediate the depolarization of postsynaptic neurons at fast excitatory synapses and are thought to regulate transmitter release from presynaptic terminals of some cell types. In addition, they have been implicated in neuronal cell death associated with anoxia and hyperexcitation. Although much has been learned about glutamate receptors in the past 10 years, many aspects of their function remain poorly understood. The long term objective of the proposed research is to provide a better understanding of excitatory synaptic transmission by characterizing the operation of receptors and channels that are activated by glutamate. A second major goal is to uncover properties of the channels that may allow for clinical intervention to prevent excitotoxic cell death. Patch clamp techniques will be used to record the whole-cell and single channel currents evoked by excitatory amino acids in neurons maintained in primary cell culture and in freshly dissociated cells from peripheral sensory ganglia or from the CNS. The work involves two main projects. The first set of experiments will test the hypothesis that negative charges on the external face of the N-methyl-D-aspartate (NMDA) receptor in central neurons contribute to its unique gating and permeation properties, including regulation of the channel by glycine, Zn, polyamines, protons, Mg, and dizocilpine. The second project focuses on the activation and desensitization of non-NMDA receptors in CNS neurons and in dorsal root ganglion neurons, which express a novel form of this receptor. The specific aim is to determine the mechanism or mechanisms that underlie desensitization by studying the action of ions, drugs and proteins that are known to change the gating behavior of non-NMDA receptor channels. Another major focus of this project is to characterize the pharmacology of receptors expressed by DRG neurons with the goal of finding selective agents that can distinguish between the central and peripheral forms of the receptor. Such agents will be critical for establishing the function of the DRG receptor; they also might prove capable of controlling the sensation of pain, because the expression of this receptor in DRGs appears to be restricted to nociceptive neurons.