A New Family of Voltage-gated Potassium Channel Regulaory Subunits

描述（由申请人提供）：电压门控钾通道调节亚基的新家族辅助亚基和调节修饰是体内电压门控钾（Kv）通道实现正常功能所必需的。原因很清楚。辅助亚基和调节修饰（如磷酸化）改变孔形成亚基以确定混合复合物的组织特异性蛋白质表达、门控动力学、单位电导、离子选择性、调节和药理学。因此，已经看到辅助亚基和调节基序中的疾病相关突变引起危及生命的心律失常、神经肌肉疾病如癫痫和周期性麻痹。本申请是基于我们最近的工作，证明了普遍存在的、小的、泛素相关的修饰蛋白（SUMO，~ 100个氨基酸）是一类未被识别的辅助亚基，其通过质膜中的可逆共价修饰来调节钾通道。该应用基于表明SUMO通过Kv2.1、Kv4.3和KChlP 2的修改和调节直接影响激发的初步数据。拟议的研究旨在描述SUMO通路的机制细节，并阐明通过实验细胞中的克隆通道和大鼠脑原代细胞中的天然电流的实验对生理学的影响。我们认为，Kv通道的SUMO化调节值得这样的审查，因为（a）它似乎是重要的正常生理;（B）一个新的离子通道调节机制将被阐明;和（c）辅助亚基/调节修饰的研究已经为基础的诊断和治疗干预措施，以改善人类健康。修订后的申请旨在解决第一个审查周期中提出的问题。

DESCRIPTION (provided by applicant): A New Family of Voltage-gated Potassium Channel Regulatory Subunits Accessory subunits and regulatory modifications are required to achieve normal function of voltage-gated potassium (Kv) channels in vivo. The reasons are clear. Accessory subunits and regulatory modifications (such as phosphorylation) alter pore-forming subunits to determine tissue specific protein expression, gating kinetics, unitary conductance, ion selectivity, regulation and pharmacology of mixed complexes. Thus, disease-associated mutations in accessory subunits and regulatory motifs have been seen to cause life- threatening cardiac arrhythmias, neuromuscular diseases like epilepsy and periodic paralysis. This application is based on our recent work demonstrating that the ubiquitous, small, ubiquitin-related modifier proteins (SUMOs, -100 amino acids) are an unrecognized class of accessory subunits that regulate potassium channels by reversible covalent modification in the plasma membrane. This application is based on preliminary data indicating that SUMOs directly influence excitation by modification and regulation of the Kv2.1, Kv4.3 and KChlP2. The proposed studies seek to describe regulation of these Kv channels by the SUMO pathway in mechanistic detail and to elucidate effects on physiology through experiments of cloned channels in experimental cells and native currents in primary cells from rat brain. We argue Kv channel regulation by sumoylation merits such scrutiny because (a) it appears to be important to normal physiology; (b) a new mechanism of ion channel regulation will be elucidated; and, (c) studies of accessory subunits/regulatory modifications have been the basis for diagnostic and therapeutic interventions to improve human health. This revised application seeks to address concerns raised in the first review cycle.