Role of 4.1 proteins in kainate receptor localization and function

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中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基本组成部分，因此它们可能比AMPA或NMDA受体更容易成为药物靶点。KARs在不同神经元群体中的显著异质性分布部分地使其调节作用得以发挥。指导KAR极化分布和突触（或突触外）靶向的神经元特异性细胞机制在很大程度上仍然未知。我们的长期目标是阐明的分子过程，控制组成和调节KAR定位在神经元。我们发现Epb4.1蛋白通过与受体亚基羧基端保守区域的相互作用改变神经元KAR的定位和功能。在这个项目中，我们将确定该协会的网站（S）和亚基特异性，如何4.1蛋白控制KAR在神经元中的定位，并确定如何翻译后修饰，如棕榈酰化和磷酸化调节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的目标，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。 公共卫生相关性：红藻氨酸受体是影响哺乳动物脑中兴奋和抑制系统之间平衡的多功能蛋白质。控制它们在大脑中合成和定位的细胞机制知之甚少，但这些过程对于受体蛋白的正常功能至关重要。在这项研究中，我们将阐明一组细胞内蛋白质在移动红藻氨酸受体到其在神经元中的功能活性位点中的作用。

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. PUBLIC HEALTH RELEVANCE: Kainate receptors are multifunctional proteins that influence the balance between excitatory and inhibitory systems in the mammalian brain. The cellular mechanisms that control their synthesis and localization in the brain are poorly understood, but these processes are critical for the normal functioning of the receptor proteins. In this grant, we will elucidate the role of a set of intracellular proteins in moving kainate receptors to their site(s) of functional activity in neurons.