Functional and structural dynamics of KCNH4 and KCNH8

KCNH4 和 KCNH8 的功能和结构动力学

基本信息

批准号：
10445688
负责人：
William N Zagotta
金额：
$ 15.55万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10445688
关键词：
Action Potentials Affect Amino Acids Antibodies Architecture Arrhythmia Binding Brain Cells Chemosensitization Cognition Cognitive deficits Crystallization Cyclic Nucleotides DNA Sequence Alteration DNA biosynthesis Defect Disease Electrophysiology (science)Ethers Family Family member Fluorescence Fluorescence Resonance Energy Transfer Fluorescence Spectroscopy Fluorometry Future Genes Goals Health Heart Heart Abnormalities Heart Diseases Human Ion Channel Ions Laboratories Ligands Link Lipids Long QT Syndrome Malignant Neoplasms Measures Membrane Mental disorders Methods Modeling Molecular Conformation Movement Neurons Phosphatidylinositol 4,5-Diphosphate Physiological Play Positioning Attribute Potassium Channel Process Property Protein Isoforms Regulation Resolution Roentgen Rays Role Shapes Signal Transduction Small Interfering RNA Structure Time Transition Elements Ventricular environmental change experimental study member molecular rearrangement neoplastic cell patch clamp response schizophrenia risk sensor sudden cardiac death therapy development voltage

项目摘要

Abstract Ion channels underlie all electrical excitability in the brain and heart, and defects in ion channels are the cause of many human disorders. The KCNH family of channels, ERG, ELK, and EAG, are voltage-dependent potassium channels that are specialized for their role in shaping the electrical activity of cells. Defects in KCNH channels have been shown to be linked to cognitive defects, increased risk of schizophrenia, cardiac arrhythmias, and cancer. Given their importance, it is surprising that some of the KCNH family members are considered “understudied”. The goal of this proposal is to study the functional and structural dynamics of the understudied KCNH4 and KCNH8 channels to lay the groundwork for future studies on the potential role of these channels in human health and disease. Previously we have performed many structural and functional experiments on KCNH and related channels and invented ground-breaking new fluorescence methods that allow us to record molecular rearrangements in intact channels simultaneous with electrophysiological recording. We propose to apply these methods to measure the functional and structural dynamics of KCNH4 and KCNH8 channels. These experiments will lead to the first dynamic picture of these understudied channels.

抽象的离子通道是大脑和心脏所有电兴奋性以及离子缺陷的基础通道是许多人类疾病的原因 KCNH 通道家族、ERG、 ELK 和 EAG 是电压依赖性钾通道，专门用于其 KCNH 通道缺陷在塑造细胞电活动中的作用。研究显示与认知缺陷、精神分裂症风险增加、心脏病风险增加有关鉴于心律失常和癌症的重要性，一些 KCNH 令人惊讶。家庭成员被视为“未充分研究”。该提案的目标是研究正在研究的 KCNH4 和 KCNH8 通道的功能和结构动力学为未来研究这些通道在人类中的潜在作用奠定基础之前我们已经进行了许多结构性和功能性的研究。在KCNH和相关渠道上进行实验并发明了突破性的新产品荧光方法使我们能够完整地记录分子重排我们建议将这些通道与电生理记录同时应用。测量 KCNH4 和 KCNH8 功能和结构动力学的方法这些实验将产生这些被研究对象的第一张动态图片。渠道。