A Current Regulation by Dipeptidyl Peptidase-Like Proteins

描述（由申请人提供）：二肽基肽酶样蛋白的电流调节二肽基肽酶样（DPL）蛋白DPP6和DPP10调节Kv4通道表达和功能特性，是天然神经元ISA、体树突A电流以及Kv4 α亚基和KChIP辅助亚基的重要组成部分。如果没有DPL的表达，ISA就会受到严重破坏，电流表达减少，激活和失活特性异常。在本项目中，我们将验证DPL基因前两个外显子的特定保守功能域调节DPL蛋白与Kv4通道蛋白的相互作用的假设，并确定通道复合物的功能特性。这些研究将提供关于调节神经元功能特性的分子机制的重要新信息，并可能对我们理解诸如ALS、自闭症谱系障碍、哮喘等疾病过程的分子机制以及DPL蛋白所涉及的其他调节途径具有重要意义。在这个项目中，我们将解决以下目标，以更好地了解DPL蛋白调节A电流的分子机制。目的1：验证DPP6a和DPP10a使用与其他n型失活结构域具有共同潜在分子机制的新型n端基序加速失活的假设。目的2：验证DPP6a和DPP10a在n型失活过程中经历多个中间状态的假设。目的3：验证跨膜和跨膜周围区域特异性DPL残基调节Kv4通道激活门控的假设。

DESCRIPTION (provided by applicant): A Current Regulation by Dipeptidyl Peptidase-Like Proteins Dipeptidyl peptidase like (DPL) proteins, DPP6 and DPP10, regulate Kv4 channel expression and functional properties and are essential components of the native neuronal ISA, somatodendritic A current along with Kv4 alpha subunits and KChIP auxiliary subunits. Without DPL expression, ISA is severely disrupted with reduced current expression and abnormal activation and inactivation properties. In this project we will test the hypothesis that specific conserved functional domains in the first two exons of DPL genes regulate the interaction of DPL proteins with Kv4 channels proteins and determine the functional properties of the channel complex. These studies will provide important new information about the molecular mechanisms that regulate the functional properties of neurons and likely will be important for our understanding of the molecular mechanisms underlying disease processes such as ALS, autism spectrum disorder, asthma, and other regulatory pathways that DPL proteins have been implicated in. In this project we will address the following aims to better understand the molecular mechanisms involved in the regulation of A currents by DPL proteins. Aim 1: Test the hypothesis that DPP6a and DPP10a accelerate inactivation using a novel N-terminal motif that shares a common underlying molecular mechanism with other N-type inactivation domains. Aim 2: Test the Hypothesis that multiple intermediate states are experienced during N-type inactivation by DPP6a and DPP10a. Aim 3: Test the hypothesis that specific DPL residues in transmembrane and peri-transmembrane region modulate Kv4 channel activation gating. PUBLIC HEALTH RELEVANCE: Dipeptidyl peptidase-like (DPL) proteins are expressed at high levels in the brain and human genetic linkage studies have linked DPL genetic variations to asthma, amyotropic lateral sclerosis, and autism spectrum disorders. A known function of DPL proteins is to bind and regulate potassium channels. In this project we will characterize the molecular mechanisms that underlie the regulation of potassium channels by DPL proteins.