Towards understanding the role of sumoylation in ion channel regulation

描述（由申请人提供）： 研究：离子通道蛋白作为门控制离子进出细胞的流量。它们的功能对于细胞电活动以及电解质稳态是必不可少的。紧密调节是离子通道功能的标志，其对于微调细胞兴奋性至关重要。我们的实验室最近确定了一种新的离子通道调控机制，涉及可逆的肽连接（sumoylation），以前已知介导核输入/输出和转录。一个小的泛素样修饰蛋白SUMO-1的共价修饰阻止了背景钾通道K2 P1通过钾离子。本研究的目的是探讨SUMO是否调节电压门控钾通道。我们提出了SUMO介导的抑制两个电压门控钾通道，Kv2.1和Kv4.3的初步证据。Kv2.1的阻断与引发胰腺β细胞中的葡萄糖依赖性胰岛素分泌有关。Kv4.3表达的改变已在心力衰竭中得到证实。建议的再研究计划旨在扩大的理解，sumoylation作为一个生理相关的调节机制，与各种分子，生物化学和电生理学方法的帮助。将详细研究Kv4.3和Kv2.1的SUMO调节，包括修饰位点的鉴定、SUMO对上述通道产生的电流的影响以及修饰途径的特定组分的表征。将在其大量表达的胰腺β细胞中研究Kv2.1的类小泛素化。 候选人：Sindhu Rajan博士在博士期间接受了离子通道生物学家的培训，这促使她决定在Steve Goldstein博士的实验室进行博士后研究。她的职业目标是做基础研究，研究离子通道功能和功能障碍。提交该提案是为了支持她的职业发展，并帮助她成为一名学术上可行的独立调查员。 环境：候选人的导师Steve Goldstein博士是钾通道研究和离子通道疾病的主要研究者，他的实验室拥有丰富的分子生物学，生物化学和生物物理专业知识。芝加哥大学的儿科学、神经生物学、药理学和生理学系包括国际公认的离子通道研究骨干。

DESCRIPTION (provided by applicant): The Research: Ion channel proteins act as gates controlling the flux of ions in and out of cells. Their function is essential for cellular electrical activity as well as electrolyte homeostasis. Tight regulation is a hallmark of ion channel function that is vital for fine tuning cellular excitability. Our laboratory recently identified a novel ion channel regulatory mechanism involving reversible peptide linkage (sumoylation) that had been previously known to mediate nuclear import/export and transcription. Covalent modification by a small ubiquitin-like modifier protein, SUMO-1, prevented the background potassium channel, K2P1, from passing potassium ions. The goal of this study is to investigate whether SUMO regulates volatge gated potassium channels. We present preliminary evidence for SUMO mediated inhibition of two voltage gated potassium channels, Kv2.1 and Kv4.3. Blockage of Kv2.1 has been implicated in eliciting glucose-dependent insulin secretion in pancreatic beta cells. Altered Kv4.3 expression has been demonstrated in heart failure. The proposed reasearch plan aims at expanding the understanding of sumoylation as a physiologically relevant regulatory mechanism with the help of various molecular, biochemical and electrophysiological methods. SUMO modulation of Kv4.3 and Kv2.1 will be studied in detail, including identification of modification sites, the effect of SUMO on currents generated by the aforementioned channels, and characterization of specific components of the modification pathway. Sumoylation of Kv2.1 will be studied in pancreatic beta cells where it is abundantly expressed. The candidate: Dr. Sindhu Rajan trained as an ion channel biologist during her Ph.D, which motivated her decision to pursue post-doctoral research in Dr. Steve Goldstein's laboratory. Her career goal is to do basic research, investigating ion channel function and dysfunction. This proposal is submitted to support her career development and help enable her to become an academically viable independent investigator. The environment: The candidate's mentor Dr. Steve Goldstein is a leading investigator in potassium channel research and ion channel diseases and his laboratory is rich in molecular biology, biochemistry and biophysical expertise. The Departments of Pediatrics, Neurobiology, Pharmacology and Physiology at the University of Chicago include an internationally recognized cadre of ion channel researchers.