Regulation of Ionotropic Glutamate Receptors

离子型谷氨酸受体的调节

• 批准号: 7423984
• 负责人: STEVEN J TAVALIN
• 金额: $ 22.41万
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7423984
• 关键词: A kinase anchoring protein; AMPA Receptors; Address; Architecture; Binding; Biochemical; Calcineurin; Calmodulin; Cells; Complex; Cyclic AMP-Dependent Protein Kinases; DLG1 gene; Data; Dependence; Development; Dominant-Negative Mutation; Drug abuse; Ensure; Enzymes; Family; Glutamate Receptor; Glutamates; Goals; Hippocampus (Brain); In Vitro; Ion Channel; Lead; Learning; Link; Location; Long-Term Depression; Long-Term Potentiation; Mediating; Membrane; Memory; Mental disorders; Methods; Modification; Molecular; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Neurotransmitters; Operative Surgical Procedures; Output; Pain; Pattern; Phospholipids; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Protein Dephosphorylation; Protein Kinase; Protein phosphatase; Proteins; Recombinants; Recruitment Activity; Regulation; Rodent; Role; Scaffolding Protein; Second Messenger Systems; Shapes; Signal Transduction; Signaling Protein; Site; Stroke; Synapses; Synaptic Transmission; Synaptic plasticity; System; Techniques; Testing; Thinking; Transcriptional Activation; Up-Regulation; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; base; member; mutant; nervous system disorder; neurotransmission; novel therapeutics; postsynaptic; receptor; receptor function; research study; response; second messenger; spatiotemporal; synaptic function; therapeutic target

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(申请人提供)：AMPA受体(AMPAR)亚型的离子型谷氨酸受体介导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。从病理生理学角度看，这些受体可能导致神经退行性变、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过程中，GluR1AMPAR亚单位的磷酸化状态似乎是一个共同的调节目标。因此，了解细胞内信号如何被转导来调节GluR1的磷酸化是很重要的。A-激酶锚定蛋白AKAP79(啮齿类动物的AKAP150)与几个第二信使激活的信号蛋白有关，包括cAMP依赖的蛋白激酶(PKA)、钙(2+)依赖的蛋白磷酸酶PP2B(CaN[CaN])、钙(2+)、磷脂依赖的蛋白激酶(PKC)和钙调素(CaM)。AKAP79通过与SAP97相互作用靶向GluR1，SAP97是Maguk家族突触支架蛋白的成员。最近的数据表明，AKAP79促进了PKA和CaN介导的GluR1AMPA受体的调节；然而，该复合体的其余成分调节AMPAR的能力仍未完全解决。我们将使用生化、电生理和分子方法来确定AKAP79如何影响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调节中的作用；3)AKAP150锚定的PKC对天然AMPA受体的调节作用。了解AKAP79/150信号复合体的基本操作可能会为治疗神经疾病和中风带来新的治疗靶点。

项目成果

Auxiliary beta subunits differentially determine pka utilization of distinct regulatory sites on Cav1.3 L type Ca2+ channels.

辅助 β 亚基差异性地决定 Cav1.3 L 型 Ca2 通道上不同调节位点的 pka 利用。

• DOI: 10.4161/chan.4284
• 发表时间: 2007
• 期刊: Channels (Austin, Tex.)
• 作者: Liang,Yixin;Tavalin,StevenJ
• 通讯作者: Tavalin,StevenJ

Tyrosine phosphorylation regulates the endocytosis and surface expression of GluN3A-containing NMDA receptors.

• DOI: 10.1523/jneurosci.2721-12.2013
• 发表时间: 2013-02-27
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Chowdhury D;Marco S;Brooks IM;Zandueta A;Rao Y;Haucke V;Wesseling JF;Tavalin SJ;Pérez-Otaño I
• 通讯作者: Pérez-Otaño I