The influence of beta-subunits and sphingomyelin on sodium channel function

β亚基和鞘磷脂对钠通道功能的影响

• 批准号: 8448949
• 负责人: Frank Gert Werner Bosmans
• 金额: $ 24.9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448949
• 关键词: Address; Affinity; Animals; Arrhythmia; Behavior; Biochemical; Biodiversity; Cell membrane; Characteristics; Chimera organism; Complex; Data; Disease; Epilepsy; Goals; Grant; Human body; Indium; Instruction; Ion Channel; Label; Lipids; Medical; Membrane; Membrane Lipids; Modification; Molecular; Movement; Muscle Weakness; Mutation; Pain; Permeability; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Point Mutation; Positioning Attribute; Predisposition; Protein Isoforms; Proteins; Recruitment Activity; Reporter; Role; Shapes; Signal Transduction; Sodium; Sodium Channel; Sphingomyelins; Structure; Syndrome; Techniques; Testing; Therapeutic; Toxin; Training; Transplantation; United States National Institutes of Health; Universities; Wisconsin; Work; insight; novel; novel strategies; protein complex; sensor; skills; voltage; voltage clamp

Voltage-activated sodium (Nav) channels are found throughout the human body where they form the cornerstones of fast electrical signaling by regulating the Na+ permeability ofthe cell membrane. As such, Nav channels are among the most widely targeted ion channels by both drugs and toxins. Their medical relevance is underscored by mutations that underlie debilitating disorders such as epilepsy, muscle weakness, cardiac arrhythmias and pain syndromes. Despite their physiological importance, our understanding of thes;e channels is hampered by a lack of insight into their complex structures and working mechanisms. Rather than existing as independent units, Nav channels are part of a signaling complex that involves auxiliary proteins and membrane lipids. My goal is to address fundamental questions on the identities of the Nav channel signaling complex components and to resolve their mechanisms of action at the molecular level. In particular, I will examine to what extent and by what mechanism auxiliary 3-subunits shape Nav channel gating behavior and pharmacology. Furthermore, I intend to investigate how the surrounding membrane lipids influence Nav channel function and their interaction with (3-subunits. Successful completion of my aims will reveal key elements in the Nav channel signaling complex, help define Nav channel function in normal and pathological states, and may offer novel strategies for developing therapeutic drugs.

在整个人体中都发现了电压激活的钠（NAV）通道 通过调节细胞膜的Na+渗透性，快速电信号的基石。像这样， NAV通道是药物和毒素靶向最广泛的离子通道之一。他们的医疗 相关性是由使疾病（例如癫痫，肌肉）的突变强调的 弱点，心律不齐和疼痛综合征。尽管它们的生理重要性，但我们 缺乏对其复杂结构的洞察力和工作的理解阻碍了对这些渠道的理解 机制。 NAV频道不是作为独立单元而存在的，而是信号复合体的一部分 涉及辅助蛋白和膜脂质。我的目标是解决有关的基本问题 NAV通道信号传导复杂组件的身份并解决其作用机理 分子水平。特别是，我将通过哪种机制辅助3-亚基进行检查 塑造NAV通道门控行为和药理学。此外，我打算调查 周围的膜脂质会影响NAV通道功能及其与（3套子女的相互作用）。 成功完成我的目标将揭示NAV频道信号复合体中的关键要素，帮助 在正常和病理状态下定义NAV渠道功能，并可能提供开发的新策略 治疗药物。