Subcellular Localization of Neuronal Ion Channels

描述(由申请人提供)：本基金建议的研究目的是从分子角度了解离子通道定位于神经元特定亚细胞区域的潜在机制。研究将集中于阐明Kv4和Kv1家族的电压门控K+通道定位于神经元亚细胞室和内的机制。研究目的如下：1.探讨Kv1.3在小脑浦肯野细胞内树突定位的机制。2.明确接头蛋白在Kv4.2转运和表达调控中的作用。3.用噬菌体展示抗体研究Kv4.2在皮质和海马锥体细胞树突间的定位机制。4.鉴定与Kv4.2的二亮氨酸基序相互作用并在介导该通道的树突状靶向中发挥作用的蛋白质。这项研究的最终目的是了解K+通道是如何定位到神经元中特定的亚细胞区域的。这是K+通道调节的一个重要方面，K+通道的紊乱已被证明会导致癫痫等疾病。K+通道的定位也将作为一个模型来理解蛋白质的亚细胞运输。蛋白质的亚细胞运输是神经元许多基本功能的基础，如学习和记忆。此外，错误的蛋白质运输与阿尔茨海默病和亨廷顿病等神经系统疾病有关。

DESCRIPTION (provided by applicant): The purpose of the studies proposed in this grant is to understand, in molecular terms, the mechanisms underlying the localization of ion channels to specific subcellular regions in neurons. Studies will concentrate on elucidating the mechanisms by which the voltage-gated K+ channels from the Kv4 and Kv1 families are localized to and within subcellular compartments in neurons. The aims are as follows: 1. To investigate the mechanisms underlying dendritic localization of Kv1.3 in Purkinje cells of the cerebellum. 2. To define the role of adaptor proteins in the transport and regulation of expression of Kv4.2. 3. To use phage display antibodies to investigate the mechanisms underlying localization of Kv4.2 within the dendritic compartment of cortical and hippocampal pyramidal cells. 4. To identify proteins that interact with the dileucine motif of Kv4.2 and play a role in mediating dendritic targeting of the channel. The ultimate goal of this research is to understand how K+ channels are localized to specific subcellular regions in neurons. This is an important aspect of K+ channel regulation, derangements of which have been shown to lead to diseases such as epilepsy. K+ channel localization will also serve as a model to understand subcellular trafficking of proteins in general. Subcellular trafficking of proteins underlies many essential functions of neurons, such as learning and memory. In addition faulty protein trafficking has been linked to such neurological diseases as Alzheimer's disease and Huntington's disease.