K+ channel complexes: assembly, trafficking and function

K 通道复合物：组装、运输和功能

• 批准号: 8389665
• 负责人: WILLIAM R KOBERTZ
• 金额: $ 32.89万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 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/8389665
• 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

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.

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适当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+通道共组装，提供在多种细胞和组织中发挥功能所需的电多样性。 该提案研究了KCNQ 1-KCNE K+通道复合物，该复合物使钾进入内淋巴，维持肠上皮细胞中的盐和水稳态，并产生心脏IKs电流。 本研究的目的有三：（1）建立K+通道-KCNE复合物的组装机制，并确定疾病相关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)我们将确定是否KCNE亚基不对称调节离子传导亚基使用衍生的蝎毒素和差异突变的KCNQ 1亚基的组合。