RUI: Mechanisms of Deactivation in Sodium Channels

RUI：钠通道失活机制

• 批准号: 0235358
• 负责人: James Groome
• 金额: --
• 依托单位: Harvey Mudd College
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0235358&HistoricalAwards=false
• 关键词: RUI; Mechanisms; Deactivation; Sodium; Channels

Action potentials transmit the information of excitable cells. Voltage-sensitive sodium channels play a major role in cell excitability. Our understanding of the means by which electrically excitable cells communicate information is enhanced with a molecular approach to the function of voltage-gated ion channels. Sodium channels provide the trigger for the upstroke of the action potential by opening in response to membrane depolarization; open channels permit sodium influx whereas closed or inactivated channels do not. Excitability is regulated by two forms of channel deactivation, or closure; channel availability is dependent on deactivation of inactivated channels, and sodium influx during the falling phase of the action potential depends on deactivation of open channels. The Groome laboratory is interested in determining the structural bases of deactivation and its relation to muscle fiber excitability. In this proposal, the investigator will test the hypothesis that positively charged residues in voltage-sensing S4 segments in domains III and IV of the hNaV1.4 channel interact with negatively charged residues in the inactivation linker between those same two domains to regulate deactivation gating. Site directed mutagenesis and patch clamp electrophysiology as complementary approaches described in this proposal will provide a diversity of research opportunities to undergraduate students interested in molecular biology and neurobiology. The inter-dependent projects described in this proposal will provide excellent preparation for junior and senior students for graduate school or careers in the medical profession. The experimental plan will draw heavily on the curricular strengths of the Biology Department and will support recently developed courses in the Biology curriculum.

动作电位传递可兴奋细胞的信息。电压敏感性钠通道在细胞兴奋性中起主要作用。 我们对电兴奋细胞传递信息的方式的理解随着电压门控离子通道功能的分子方法而增强。钠通道通过响应于膜去极化而打开来提供动作电位上行的触发;开放的通道允许钠内流，而闭合或失活的通道不允许。兴奋性由两种形式的通道失活或关闭调节;通道可用性取决于失活通道的失活，而动作电位下降期的钠内流取决于开放通道的失活。Groome实验室有兴趣确定失活的结构基础及其与肌纤维兴奋性的关系。在本提案中，研究者将检验以下假设：hNaV1.4通道结构域III和IV中电压敏感S4片段中的带正电荷残基与这两个结构域之间失活连接子中的带负电荷残基相互作用，以调节失活门控。 定点诱变和膜片钳电生理学作为补充方法，在这个建议中所描述的将提供多样性的研究机会，对分子生物学和神经生物学感兴趣的本科生。 本建议书中所描述的相互依赖的项目将为大三和大四学生在医学专业的研究生院或职业生涯提供良好的准备。 实验计划将在很大程度上利用生物系的课程优势，并将支持生物课程中最近开发的课程。