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，DPP 6和DPP 10，调节Kv 4通道表达和功能特性，并且是天然神经元伊萨，体树突A电流沿着Kv 4 α亚基和KChIP辅助亚基的基本组分。在没有DPL表达的情况下，伊萨被严重破坏，电流表达减少，激活和失活特性异常。在这个项目中，我们将测试的假设，在DPL基因的前两个外显子的特定保守的功能域调节DPL蛋白与Kv 4通道蛋白的相互作用，并确定通道复合物的功能特性。这些研究将提供有关调节神经元功能特性的分子机制的重要新信息，并且可能对于我们理解疾病过程的分子机制（如ALS，自闭症谱系障碍，哮喘和DPL蛋白质涉及的其他调节途径）非常重要。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。目标1：测试假设，DPP 6a和DPP 10a加速失活使用一种新的N-末端基序，共享一个共同的潜在的分子机制与其他N-型失活域。目的2：验证DPP 6a和DPP 10a在N型失活过程中经历多个中间状态的假设。目的3：验证跨膜区和跨膜区特异性DPL残基调节Kv 4通道激活门控的假设。 公共卫生相关性：二肽基肽酶样（DPL）蛋白在大脑中高水平表达，人类遗传连锁研究已将DPL遗传变异与哮喘、肌萎缩侧索硬化症和自闭症谱系障碍联系起来。DPL蛋白的已知功能是结合和调节钾通道。在这个项目中，我们将表征DPL蛋白调节钾通道的分子机制。

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.