Mechanisms of Ethanol Action on NMDA Receptors and LTP

乙醇对 NMDA 受体和 LTP 的作用机制

• 批准号: 6646386
• 负责人: Rachel Marie Alvestad Linger
• 金额: $ 2.58万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6646386
• 关键词: NMDA receptors; cognition; electrophysiology; endocytosis; ethanol; glutamate receptor; hippocampus; immunoprecipitation; kinase inhibitor; laboratory rat; long term potentiation; phosphatase inhibitor; phosphorylation; predoctoral investigator; tissue /cell culture; tyrosine; western blottings

DESCRIPTION (provided by applicant): N-methyl D-aspartate receptors (NMDARs) are ionotropic glutamate receptors required for induction of LTP in area CA1 of the hippocampus. In the 1980's, it was discovered that ethanol inhibits these receptors and blocks LTP. The mechanism(s) by which ethanol inhibits NMDARs and LTP have not been elucidated. We have previously shown that PKC activators induce tyrosine phosphorylation and potentiation of the NMDAR. Phosphorylation is also required for LTP induction. We hypothesized that the inhibitory action of ethanol may be a result of reduced tyrosine phosphorylation of NMDAR subunits leading to endocytosis of NMDARs. In order to test these hypotheses, we will use the hippocampal slice preparation, immunoprecipitation, and western blotting to evaluate tyrosine phosphorylation of NMDA subunits following in situ ethanol exposure. Additionally, we will study NMDAR function and LTP induction utilizing electrophysiology. Biochemical methods will be employed to evaluate the surface expression of NMDARs. We hope that these studies will contribute to the understanding of alcoholism by enhancing our knowledge of how ethanol affects cognition.

描述（由申请人提供）：n -甲基d -天冬氨酸受体（NMDARs）是海马CA1区诱导LTP所需的离子性谷氨酸受体。在20世纪80年代，人们发现乙醇可以抑制这些受体并阻断LTP。乙醇抑制NMDARs和LTP的机制尚未阐明。我们之前已经证明PKC激活剂诱导酪氨酸磷酸化和NMDAR增强。LTP的诱导也需要磷酸化。我们假设乙醇的抑制作用可能是NMDAR亚基酪氨酸磷酸化减少导致NMDAR内吞的结果。为了验证这些假设，我们将使用海马切片制备，免疫沉淀和western blotting来评估原位乙醇暴露后NMDA亚基的酪氨酸磷酸化。此外，我们将利用电生理学研究NMDAR功能和LTP诱导。将采用生化方法评价NMDARs的表面表达。我们希望这些研究将有助于通过提高我们对乙醇如何影响认知的认识来理解酒精中毒。