Regulation of Ionotropic Glutamate Receptors

离子型谷氨酸受体的调节

• 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
• 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

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多数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修饰被认为有助于学习、记忆和神经元发育。在病理生理学上，这些受体可能导致神经变性、神经创伤、疼痛、精神障碍和药物滥用。GluR 1 AMPAR亚基的磷酸化状态似乎是这些不同形式的突触可塑性调节的共同目标。因此，重要的是要了解细胞内信号是如何转导调节GluR 1磷酸化。A激酶锚定蛋白AKAP 79（啮齿动物中的AKAP 150）与几种第二信使激活的信号传导蛋白相关，包括cAMP依赖性蛋白激酶（PKA）、Ca（2+）依赖性蛋白磷酸酶PP 2 B（钙调磷酸酶[CaN]）以及Ca（2+）和磷脂依赖性蛋白激酶（PKC）和钙调蛋白（CaM）。AKAP 79通过与突触支架蛋白的MAGUK家族成员SAP 97相互作用靶向GluR 1。最近的数据表明，AKAP 79促进PKA和CaN介导的调节GluR 1 AMPA受体;然而，该复合物的其余组分调节AMPAR的能力仍有待充分解决。利用生物化学、电生理学和分子生物学方法，我们将通过以下研究来确定AKAP 79如何形成AMPAR介导的反应：1）AKAP 79锚定的PKC对重组GluR 1磷酸化和功能的调节，2）Ca（2+）/CaM在AKAP 79介导的GluR 1调节中的作用，3）AKAP 150锚定的PKC对天然AMPA受体调节的贡献。了解AKAP 79/150信号复合物的基本运作可能会导致治疗神经系统疾病和中风的新的治疗靶点。