K+ channel complexes: assembly, trafficking and function

K 通道复合物：组装、运输和功能

基本信息

批准号：
8197788
负责人：
WILLIAM R KOBERTZ
金额：
$ 34.08万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197788
关键词：
Affect Auditory Biogenesis Biological Assay Cardiac Cells Complex Cysteine Defect Disease Endolymph Endoplasmic Reticulum Ensure Epithelial Epithelial Cells Equilibrium Family Goals Heart Heart Diseases Homeostasis In Vitro Individual Inherited Ion Channel Ions Label Lead Length Location Long QT Syndrome Lung diseases Measures Membrane Membrane Potentials Microsomes Molecular Multiprotein Complexes Muscle Mutate Mutation Neurologic Neurons Pathway interactions Peptides Physiological Physiological Processes Positioning Attribute Potassium Potassium Channel Property Proteins Radial Reagent Relative (related person)Research Scorpions Signal Transduction Sodium Chloride Structure Sulfhydryl Compounds Tissues Toxin Translations Voltage-Gated Potassium Channel Water Work base disease-causing mutation heart rhythm intestinal epithelium mutant prevent public health relevance sensor stoichiometry trafficking voltage

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this research is to elucidate the molecular and cellular mechanisms that ensure potassium (K+) channels assemble with the appropriate membrane-embedded regulatory subunits for proper physiological function. The KCNE regulatory subunits are a class of type 1 transmembrane peptides that co-assemble with tetrameric voltage-gated K+ channels, providing the electrical diversity needed to function in a wide-variety of cells and tissues. This proposal investigates KCNQ1-KCNE K+ channel complexes that enable potassium ingress into the endolymph, maintain salt and water homeostasis in intestinal epithelia, and generate the cardiac IKs current. There are three aims to this proposal: (1) We will establish assembly mechanisms for K+ channel-KCNE complexes with structurally different tetramerization domains and determine how the disease-associated mutations directly affect co-assembly. (2) We will determine the quaternary structures of misassembled K+ channel subunits in the endoplasmic reticulum. (3) We will determine whether KCNE subunits asymmetrically modulate the ion-conducting subunits using a combination of derivatized scorpion toxins and differentially-mutated KCNQ1 subunits. PUBLIC HEALTH RELEVANCE: Potassium (K+) channels function as macromolecular protein complexes composed of membrane-embedded ion-conducting and regulatory subunits. Mutations that prevent the assembly, trafficking or function of these complexes give rise to neurological, cardiac, muscular, auditory, and respiratory diseases. By investigating the molecular and cellular mechanisms that ensure the assembly, trafficking and function of K+ channel complexes, we aim to understand how these proteins work in healthy individuals and provide alternative strategies for remedying those affected by channelopathies (ion channel-related diseases).

描述（由申请人提供）：本研究的长期目标是阐明确保钾 (K+) 通道与适当的膜嵌入调节亚基组装以实现正常生理功能的分子和细胞机制。 KCNE 调节亚基是一类 1 型跨膜肽，与四聚体电压门控 K+ 通道共同组装，提供在多种细胞和组织中发挥作用所需的电多样性。该提案研究了 KCNQ1-KCNE K+ 通道复合物，该复合物使钾能够进入内淋巴，维持肠上皮细胞中盐和水的稳态，并产生心脏 IK 电流。该提案有三个目标：（1）我们将建立具有结构不同的四聚化结构域的K+通道-KCNE复合物的组装机制，并确定与疾病相关的突变如何直接影响共组装。 (2)我们将确定内质网中错误组装的K+通道亚基的四级结构。 (3)我们将使用衍生化的蝎毒素和差异突变的KCNQ1亚基的组合来确定KCNE亚基是否不对称地调节离子传导亚基。公共健康相关性：钾 (K+) 通道作为由膜嵌入的离子传导和调节亚基组成的大分子蛋白质复合物发挥作用。阻止这些复合物的组装、运输或功能的突变会引起神经、心脏、肌肉、听觉和呼吸系统疾病。通过研究确保 K+ 通道复合物组装、运输和功能的分子和细胞机制，我们旨在了解这些蛋白质如何在健康个体中发挥作用，并为治疗受通道病（离子通道相关疾病）影响的患者提供替代策略。