A New Family of Voltage-gated Potassium Channel Regulaory Subunits

描述（由申请人提供）：一个新的电压门控钾通道调节亚基家族需要辅助亚基和调节修饰来实现体内电压门控钾（Kv）通道的正常功能。原因很清楚。辅助亚基和调节修饰（如磷酸化）改变孔隙形成亚基，以确定混合复合物的组织特异性蛋白质表达、门控动力学、单一电导、离子选择性、调节和药理学。因此，辅助亚基和调节基序的疾病相关突变已被视为导致危及生命的心律失常、癫痫和周期性麻痹等神经肌肉疾病。这项应用是基于我们最近的工作，证明无处不在的小的泛素相关修饰蛋白（sumo， -100氨基酸）是一类未被识别的辅助亚基，通过质膜中可逆的共价修饰来调节钾通道。这项应用是基于初步数据，表明sumo通过修改和调节Kv2.1、Kv4.3和KChlP2直接影响激励。本研究旨在详细描述SUMO通路对这些Kv通道的调控机制，并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来阐明其对生理学的影响。我们认为，通过sumoylation调节Kv通道值得这样的审查，因为(a)它似乎对正常生理很重要；(b)阐明离子通道调控的新机制；(c)对附属亚基/调控修饰的研究已成为改善人类健康的诊断和治疗干预措施的基础。修订后的申请旨在解决在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.