Regulation of Ionotropic Glutamate Receptors

描述（由申请人提供）：AMPA受体（AMPAR）亚型的嗜离子性谷氨酸受体介导了哺乳动物中枢神经系统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修饰被认为有助于学习、记忆和神经元发育。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。在这些不同形式的突触可塑性中，GluR1 AMPAR亚基的磷酸化状态似乎是一个共同的调控目标。因此，了解细胞内信号如何被转导来调节GluR1磷酸化是很重要的。a -激酶锚定蛋白AKAP79（啮齿动物中的AKAP150）与多种第二信使激活信号蛋白相关，包括camp依赖性蛋白激酶（PKA）、Ca（2+）依赖性蛋白磷酸酶PP2B （calcineurin [CaN]）、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的相互作用靶向GluR1。最近的数据表明，AKAP79促进pka和can介导的GluR1 AMPA受体的调节；然而，该复合体的其余成分调节ampar的能力仍有待充分研究。利用生化、电生理和分子方法，我们将定义AKAP79如何塑造AMPA介导的反应，通过检查：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调节中的作用，以及3)akap150锚定的PKC对天然AMPA受体调节的贡献。了解AKAP79/150信号复合体的基本运作可能会为神经系统疾病和中风的治疗带来新的治疗靶点。

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.