Role of 4.1 proteins in kainate receptor localization and function

4.1 蛋白质在红藻氨酸受体定位和功能中的作用

• 批准号: 8488501
• 负责人: GEOFFREY T SWANSON
• 金额: $ 30.73万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8488501
• 关键词: AMPA Receptors; Amino Acid Sequence; Antibodies; Anxiety; Brain; Brain region; Cell membrane; Cell physiology; Cytoplasmic Tail; Drug Targeting; Elements; Endocytosis; Epilepsy; Equilibrium; Exhibits; Exocytosis; Family; Glutamate Receptor; Goals; Grant; Health; Hippocampus (Brain); Individual; Ion Channel; Kainic Acid Receptors; Mediator of activation protein; Membrane Protein Traffic; Molecular; Mutate; N-Methyl-D-Aspartate Receptors; Neuraxis; Neurons; Neurotransmitters; Peptides; Peripheral; Phosphorylation; Population; Post-Translational Protein Processing; Preparation; Process; Protein Family; Protein Isoforms; Protein Kinase C; Proteins; Role; Signal Pathway; Signal Transduction; Site; Slice; Specificity; Synapses; Synaptic Membranes; Synaptic plasticity; System; Testing; Therapeutic; base; chronic pain; clinical efficacy; computerized data processing; member; neuronal excitability; neuropathology; new therapeutic target; palmitoylation; postsynaptic; preclinical efficacy; presynaptic; protein 4.1; receptor; research study; stoichiometry; trafficking; transmission process

DESCRIPTION (provided by applicant): Kainate receptors (KARs) are a family of ionotropic glutamate receptors whose primary function is to help maintain the critical balance between excitatory and inhibitory processes in the central nervous system. Because KARs are primarily serve modulatory roles, rather than underlying integral components of basic excitatory transmission, they may prove more approachable drug targets than AMPA or NMDA receptors. KARs subserve their modulatory role in part by virtue of a remarkably heterogeneous distribution in different neuronal populations. The neuron-specific cellular mechanisms that direct polarized distribution and synaptic (or extrasynaptic) targeting of KARs remain largely unknown. Our long-term objective is to elucidate the molecular processes that control constitutive and regulated KAR localization in neurons. We have discovered that Epb4.1 proteins alter neuronal KAR localization and function through interactions with conserved regions of receptor subunit carboxy-terminal domains. In this project, we will identify the site(s) and subunit specificity of this association, how 4.1 proteins control localization of KARs in neurons, and determine how posttranslational modifications such as palmitoylation and phosphorylation modulate the interaction between 4.1 proteins and KAR subunits. Understanding the molecular and cellular bases for these processes is an important objective, because KARs represent new therapeutic targets for a number of neuropathologies, including chronic pain, anxiety and epilepsy.

描述（由申请人提供）：红藻氨酸受体（KAR）是离子型谷氨酸受体家族，其主要功能是帮助维持中枢神经系统兴奋性和抑制性过程之间的关键平衡。由于 KAR 主要起调节作用，而不是基本兴奋性传递的潜在组成部分，因此它们可能比 AMPA 或 NMDA 受体更容易接近的药物靶点。 KAR 发挥其调节作用的部分原因在于不同神经元群体中的显着异质分布。指导 KAR 的极化分布和突触（或突触外）靶向的神经元特异性细胞机制仍然很大程度上未知。我们的长期目标是阐明控制神经元中 KAR 的组成和调节定位的分子过程。我们发现 Epb4.1 蛋白通过与受体亚基羧基末端结构域的保守区域相互作用来改变神经元 KAR 定位和功能。在这个项目中，我们将确定这种关联的位点和亚基特异性，4.1 蛋白如何控制 KAR 在神经元中的定位，并确定棕榈酰化和磷酸化等翻译后修饰如何调节 4.1 蛋白和 KAR 亚基之间的相互作用。了解这些过程的分子和细胞基础是一个重要目标，因为 KAR 代表了许多神经病理学的新治疗靶点，包括慢性疼痛、焦虑和癫痫。