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。