Role of 4.1 proteins in kainate receptor localization and function

描述(申请人提供)：海人酸受体(KARs)是一个离子亲性谷氨酸受体家族，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。KAR在一定程度上发挥了它们的调节作用，这在一定程度上是因为它们在不同神经元群体中的分布明显不同。指导极化分布和突触(或突触外)靶向KARs的神经元特异性细胞机制在很大程度上仍不清楚。我们的长期目标是阐明控制神经元中KAR定位的构成和调控的分子过程。我们发现，Epb4.1蛋白通过与受体亚单位羧基末端结构域的保守区相互作用，改变神经元KAR的定位和功能。在这个项目中，我们将确定这种联系的位点(S)和亚基特异性，4.1蛋白如何控制KAR在神经元中的定位，并确定翻译后修饰(如棕榈酰化和磷酸化)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的目标，因为KARs代表了许多神经病理的新治疗靶点，包括慢性疼痛、焦虑和癫痫。

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.