RUI: Mechanisms of Deactivation in Sodium Channels

动作电位传递可兴奋细胞的信息。电压敏感钠离子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，通过对电压门控离子通道功能的分子方法得到了加强。钠离子通道响应膜去极化而打开，从而触发动作电位的上升；开放的通道允许钠流入，而关闭或失活的通道则不允许。兴奋性由两种形式的通道失活或关闭来调节；通道可用性取决于失活通道的失活，而动作电位下降阶段的钠流入取决于开放通道的失活。Groome实验室对确定失活的结构基础及其与肌纤维兴奋性的关系感兴趣。在本研究中，研究者将验证hNaV1.4通道III和IV结构域的电压感应S4片段的正电荷残基与这两个结构域之间的失活连接体中的负电荷残基相互作用以调节失活门控的假设。位点定向诱变和膜片钳电生理学作为本提案中描述的互补方法，将为对分子生物学和神经生物学感兴趣的本科生提供多样化的研究机会。本提案中所述的相互依存的项目将为初中生和高中生进入研究生院或从事医学专业工作提供良好的准备。实验计划将大量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。

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.