Regulation of Ionotropic Glutamate Receptors

离子型谷氨酸受体的调节

基本信息

批准号：
6983465
负责人：
STEVEN J TAVALIN
金额：
$ 23.63万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-15 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6983465
关键词：
A kinase anchoring protein AMPA receptors biological signal transduction calcium calmodulin electrophysiology glutamate receptor hippocampus laboratory rat neural plasticity phosphorylation protein isoforms protein kinase C protein protein interaction receptor expression recombinant proteins tissue /cell culture western blottings

项目摘要

DESCRIPTION (provided by applicant): The AMPA receptor (AMPAR) subtype of ionotropic glutamate receptors mediates the majority of fast excitatory neurotransmission in the mammalian central nervous system. Activity-dependent modifications in the strength of AMPAR-mediated synaptic transmission are thought to contribute to learning, memory, and neuronal development. Pathophysiologically, these receptors may contribute to neurodegeneration, neurotrauma, pain, psychiatric disorders, and drug abuse. The phosphorylation state of the GluR1 AMPAR subunit appears to be a common target for regulation during these diverse forms of synaptic plasticity. Therefore it is important to understand how intracellular signals are transduced to regulate GluR1 phosphorylation. The A-kinase-anchoring protein AKAP79 (AKAP150 in rodents) associates with several second messenger activated signaling proteins including the cAMP-dependent protein kinase (PKA), the Ca(2+)-dependent protein phosphatase PP2B (calcineurin [CaN]), and the Ca(2+) and phospholipid-dependent protein kinase (PKC) and calmodulin (CaM). AKAP79 is targeted to the GluR1 through interaction with SAP97, a member of the MAGUK family of synaptic scaffolding proteins. Recent data indicates that AKAP79 facilitates PKA-and CaN-mediated regulation of GluR1 AMPA receptors; however, the ability of the remaining components of this complex to regulate AMPARs remains to be fully addressed. Using biochemical, electrophysiological, and molecular methods, we will define how AKAP79 shapes AMPAR-mediated responses by examining: 1) regulation of recombinant GluR1 phosphorylation and function by AKAP79-anchored PKC, 2) the role of Ca(2+)/CaM in AKAP79-mediated modulation of GluR1 and 3) the contribution of AKAP150-anchored PKC towards regulation of native AMPA receptors. Understanding the basic operation of the AKAP79/150 signaling complex may lead to novel therapeutic targets for the treatment of neurological disorders and stroke.

描述（由申请人提供）：离子型谷氨酸受体的AMPA受体（AMPAR）亚型介导哺乳动物中枢神经系统中的大部分快速兴奋性神经传递。 AMPAR 介导的突触传递强度的活动依赖性改变被认为有助于学习、记忆和神经元发育。从病理生理学角度来看，这些受体可能导致神经变性、神经创伤、疼痛、精神疾病和药物滥用。 GluR1 AMPAR 亚基的磷酸化状态似乎是这些不同形式的突触可塑性过程中的共同调节目标。因此，了解细胞内信号如何转导来调节 GluR1 磷酸化非常重要。 A 激酶锚定蛋白 AKAP79（啮齿类动物中为 AKAP150）与多种第二信使激活的信号蛋白相关，包括 cAMP 依赖性蛋白激酶 (PKA)、Ca(2+) 依赖性蛋白磷酸酶 PP2B（钙调神经磷酸酶 [CaN]）、以及 Ca(2+) 和磷脂依赖性蛋白激酶 (PKC) 和钙调蛋白 (CaM)。 AKAP79 通过与突触支架蛋白 MAGUK 家族成员 SAP97 相互作用来靶向 GluR1。最近的数据表明 AKAP79 促进 PKA 和 CaN 介导的 GluR1 AMPA 受体调节；然而，该复合物的其余部分调节 AMPAR 的能力仍有待充分解决。使用生化、电生理学和分子方法，我们将通过检查以下各项来定义 AKAP79 如何塑造 AMPAR 介导的反应：1) AKAP79 锚定的 PKC 对重组 GluR1 磷酸化和功能的调节，2) Ca(2+)/CaM 在AKAP79 介导的 GluR1 调节和 3) AKAP150 锚定的 PKC 对调节天然 AMPA 受体的贡献。了解 AKAP79/150 信号复合物的基本运作可能会产生治疗神经系统疾病和中风的新治疗靶点。