Calmodulation of Auditory Potassium Channels

听觉钾通道的计算

• 批准号: 8685234
• 负责人: WILLIAM R KOBERTZ
• 金额: $ 20.94万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8685234
• 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)：钙调蛋白对听觉KCNQ通道的组装和调节都是至关重要的。尽管有许多钙调素与来自离子通道的多肽片段结合的高分辨率结构，但钙调素在功能通道上的位置以及钙诱导的与生理功能有关的结构变化对于所有的离子通道来说都是未知的。这项建议概述了一种创新的新方法，该方法可以检测KCNQ结合的钙调蛋白及其与离子传导途径的距离。利用这些实验确定的距离限制以及钾通道和钙调蛋白与多肽结合的许多高分辨结构，我们将生成不同钙化程度的KCNQ4-和KCNQ1/KCNE1-钙调蛋白复合体的四元结构。这些四级结构与拟议的功能研究相结合，将为研究耳朵中钙调节的钾循环提供前所未有的分子洞察力。