Calmodulation of Auditory Potassium Channels

听觉钾通道的计算

• 批准号: 8582774
• 负责人: WILLIAM R KOBERTZ
• 金额: $ 24.98万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8582774
• 关键词: Auditory; Binding; Biology; Calcified; Calcium; Calcium Binding; Calcium Channel; Calcium-Binding Domain; Calmodulin; Calmodulin-Binding Proteins; Chronic; Complex; Development; Disease; Ear; Endolymph; Endolymphatic Hydrops; Family; Grant; Hair Cells; High-Frequency Hearing Loss; Ion Channel; Ions; Jervell-Lange Nielsen Syndrome; Labyrinth; Lobe; Location; Membrane Potentials; Methods; Molecular; Molecular Models; Mutation; Pathway interactions; Peptide Fragments; Peptides; Physiological; Potassium; Potassium Channel; Probability; Proteins; Radial; Recycling; Regulation; Reporting; Resolution; Structure; Testing; Tinnitus; Whole-Cell Recordings; calcification; channel blockers; congenital deafness; innovation; insight; molecular modeling; mutant; novel; novel strategies; protein protein interaction; public health relevance; restraint; scaffold

DESCRIPTION (provided by applicant): Calmodulin proteins are vital for both the assembly and regulation of auditory KCNQ channels. Although there are many informative high resolution structures of calmodulin bound to peptide fragments derived from ion channels, the location of calmodulin on functioning channels and the calcium-induced structural changes responsible for physiological function have remained elusive for all ion channels. This proposal outlines an innovative new approach that detects KCNQ-bound calmodulin and its distance from the ion conduction pathway. Using these experimentally determined distance restraints and the many high resolution structures of potassium channels and calmodulin bound to peptides, we will generate quaternary structures of the differently calcified KCNQ4- and KCNQ1/KCNE1-calmodulin complexes. These quaternary structures combined with the proposed functional studies will provide unprecedented molecular insight into calcium-regulated potassium recycling in the ear.

描述（由申请人提供）：钙调蛋白对于听觉 KCNQ 通道的组装和调节至关重要。 尽管钙调蛋白与源自离子通道的肽片段结合有许多信息丰富的高分辨率结构，但钙调蛋白在功能通道上的位置以及负责生理功能的钙诱导的结构变化对于所有离子通道仍然难以捉摸。 该提案概述了一种创新的新方法，可检测 KCNQ 结合的钙调蛋白及其与离子传导通路的距离。 利用这些实验确定的距离限制以及与肽结合的钾通道和钙调蛋白的许多高分辨率结构，我们将生成不同钙化的 KCNQ4-和 KCNQ1/KCNE1-钙调蛋白复合物的四级结构。 这些四级结构与拟议的功能研究相结合，将为耳内钙调节钾循环提供前所未有的分子见解。