Molecular Components of A-type K+ channels

A 型 K 通道的分子成分

基本信息

批准号：
8671054
负责人：
Bernardo Rudy
金额：
$ 35.04万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-11 至 2015-08-31
项目状态：
已结题

项目摘要

Fast transient A-type K+ currents (IA), such as the subthreshold-activating somato-dendritic A-type K+ currents in neurons (ISA) and the fast transient outward K+ current in cardiac ventricular myocytes (Ito) are essential for the proper functioning of the brain and the heart. During pathological conditions, abnormalities in these currents can contribute to disease conditions, as recently found in a patient with temporal lobe epilepsy. This project addresses the molecular nature of the ion channels responsible for the generation of these currents in mammalian neurons. It seeks to establish the molecular composition of these channels and to elucidate the physiological significance of the identified components. Work supported by this grant led to the discovery of a novel family of proteins that associates with ISA channels known as DPPLs, of which two members are currently known DPPX (or DPP6) and DPP10. It is now believed that ISA channels in neurons are ternary complexes that include principal or pore-forming subunits of the Kv4 family and two types of associated proteins KChIPs and DPPLs. This application is focused in CA1 hippocampal pyramidal cells, neurons that are important in spatial learning and in the pathogenesis of epilepsy, and prominently express one Kv4 protein Kv4.2 and one DPPL, DPPX. The goal of the proposal is to test the hypothesis that DPPX is an important component of Kv4 channels in CA1 neurons, determining the proper distribution, biophysical properties and dynamic modulation of the channels. Aim 1 will utilize highly specific antibodies raised during the last funding period to investigate the localization of DPPX in CA1 neuron dendrites and its relationship to the other Kv4 channel components. Aim 2 will utilize DPPX knockout mice also developed during the last funding period to investigate the effects of DPPX ablation on the distribution and function of Kv4 channels in CA1 neurons. Aim 3 explores aspects of DPPX actions on Kv4 channels that have thus far received little attention: the effects of this auxiliary subunit on channel modulation by protein kinases and in controlling channel trafficking and expression in the plasma membrane, to test the hypothesis that DPPX regulates the stability of Kv4 channels at the plasma membrane. Mutations in the gene encoding DPPX have been associated with autism, underscoring the importance of understanding the function of these proteins.

快速瞬态A型K+电流（IA），例如神经元（ISA）中的子阈值激活的somato-dendritic-dendritic a型K+电流和心脏心室心肌细胞（ITO）中的快速瞬态K+电流对于大脑和心脏的正常功能至关重要。在病理条件下，这些电流异常可能导致疾病状况，这是最近在颞叶癫痫患者中发现的。该项目解决了负责哺乳动物神经元中这些电流的离子通道的分子性质。它试图建立这些通道的分子组成，并阐明已鉴定成分的生理意义。这笔赠款支持的工作导致发现了一个新型蛋白质家族，该蛋白质与ISA渠道相关联，其中两个成员目前是DPPX（或DPP6）和DPP10的著名。现在认为，神经元中的ISA通道是三元复合物，包括KV4家族的主要或形成孔的亚基以及两种相关蛋白Kchips和DPPL的类型。该应用集中在CA1海马锥体细胞，在空间学习和癫痫发病机理中很重要的神经元，并显着表达一种KV4蛋白Kv4.2和一个DPPL，DPPX。该提案的目的是检验以下假设：DPPX是CA1神经元中KV4通道的重要组成部分，确定通道的适当分布，生物物理特性和动态调制。 AIM 1将利用在最后一个资金期间提出的高度特异性抗体来研究DPPX在CA1神经元树突中的定位及其与其他KV4通道成分的关系。 AIM 2将利用在最后一个资金期间也开发的DPPX敲除小鼠，以研究DPPX消融对CA1神经元中KV4通道的分布和功能的影响。 AIM 3探讨了迄今为止关注的KV4通道上的DPPX动作的各个方面：该辅助亚基对蛋白激酶的通道调节的影响以及控制质膜中的通道运输和表达，以测试DPPX的假设，以调节DPPX的质量质量质量的稳定性。编码DPPX的基因中的突变与自闭症有关，强调了了解这些蛋白质功能的重要性。