GLUTAMATE-GATED CHANNELS IN CENTRAL & PERIPHERAL NEURO.

谷氨酸门控离子通道在细胞内的代谢中起着重要的作用。 神经系统 已知它们可介导 突触后神经元在快速兴奋性突触，并认为 调节某些细胞突触前末梢的递质释放 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 虽然很多事情 在过去的10年里，我了解了谷氨酸受体的许多方面， 它们的功能仍然知之甚少。 拟议研究的长期目标是提供一个更好的 兴奋性突触传递的理解，通过表征 谷氨酸激活的受体和通道的运作。 一 第二个主要目标是揭示通道的特性， 用于临床干预以防止兴奋性细胞死亡。 膜片钳 技术将用于记录全细胞和单通道 兴奋性氨基酸诱发的神经元电流维持在 原代细胞培养物和来自外周血的新鲜分离的细胞中 感觉神经节或中枢神经系统。 这项工作涉及两个主要项目。 第一组实验将 测试假设，负电荷的外部面的 中枢神经元的N-甲基-D-天冬氨酸（NMDA）受体参与了其调节作用。 独特的门控和渗透性能，包括调节 通道的甘氨酸，锌，多胺，质子，镁和地佐环平。 的 第二个项目侧重于非NMDA的激活和脱敏 受体在中枢神经系统神经元和背根神经节神经元， 表达这种受体的新形式。 具体目标是确定 通过研究脱敏的机制， 已知改变门控的离子、药物和蛋白质的作用 非NMDA受体通道。 另一个焦点是 该项目旨在描述DRG表达的受体的药理学特征 神经元的目标是找到选择性的代理人， 感受器的中枢和外周形式之间的联系。 此类试剂 对于确定DRG受体的功能至关重要;它们 也可能被证明能够控制疼痛的感觉，因为 该受体在DRG中的表达似乎仅限于 伤害感受神经元

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.