Towards understanding the role of sumoylation in ion channel regulation

理解苏酰化在离子通道调节中的作用

• 批准号: 7918744
• 负责人: Sindhu Rajan
• 金额: $ 12.35万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7918744
• 关键词: Amino Acids; Basic Science; Binding; Biochemical; Biochemistry; Cell Nucleus; Cell membrane; Cells; Chicago; Complex; Data; Disease; Doctor of Philosophy; Electrolytes; Environment; Enzymes; Event; Excision; Functional disorder; Genes; Genetic Transcription; Glucose; Goals; Heart failure; Homeostasis; Hormones; Human Genome; Ion Channel; Ion Channel Protein; Ions; Kidney Diseases; Knockout Mice; Kv2.1 channel; Kv4.3 channel; Laboratories; Learning; Ligase; Light; Lysine; Mediating; Mentors; Methods; Modification; Molecular; Molecular Biology; Molecular Conformation; Movement; Mutation; Neurobiology; Nuclear Import; PIAS3 Gene; Pathway interactions; Peptide Hydrolases; Peptides; Pharmacology; Physiology; Play; Postdoctoral Fellow; Potassium Channel; Principal Investigator; Proteins; Regulation; Reporting; Research; Research Personnel; Role; SUMO-1 Protein; Shapes; Signal Transduction; Site; Sodium Chloride; Stimulus; Structure of beta Cell of islet; System; Tandem Pore Domain Potassium Channels; Time; Training; Ubiquitin; Universities; Voltage-Gated Potassium Channel; adduct; base; career; career development; fascinate; in vivo; insulin secretion; nervous system disorder; neurotransmitter release; novel; pediatric department; potassium ion; prevent; programs; protein protein interaction; wasting

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.

描述(由申请人提供)： 研究：离子通道蛋白充当闸门，控制离子进出细胞的流量。它们的功能对细胞的电活动和电解质的稳态都是必不可少的。严格的调节是离子通道功能的标志，而离子通道功能对于微调细胞的兴奋性至关重要。我们的实验室最近发现了一种新的离子通道调控机制，涉及可逆肽连接(SUMO化)，此前已知该机制介导核进出口和转录。一种小的泛素样修饰物蛋白SUMO-1的共价修饰阻止了背景钾通道K2P1通过钾离子。本研究的目的是研究相扑是否调节电压门控性钾通道。我们提供了相扑介导的抑制两个电压门控性钾通道Kv2.1和Kv4.3的初步证据。阻断Kv2.1与诱导胰岛β细胞葡萄糖依赖的胰岛素分泌有关。Kv4.3的表达改变已在心力衰竭中被证明。建议的研究计划旨在通过各种分子、生化和电生理方法来扩大对苏莫化作为一种生理相关调控机制的理解。将详细研究Kv4.3和Kv2.1的相扑调制，包括修饰位点的识别，相扑对上述通道产生的电流的影响，以及修饰途径的特定成分的特征。Kv2.1的苏莫化将在大量表达Kv2.1的胰腺β细胞中进行研究。 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博士的实验室从事博士后研究。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。提交这项建议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：候选人的导师史蒂夫·戈尔茨坦博士是钾通道研究和离子通道疾病方面的领先研究员，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、神经生物学、药理学和生理学系包括一批国际公认的离子通道研究人员。