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Molecular bases of BK channel function and localization

BK通道功能和定位的分子基础

基本信息

批准号：
7783438
负责人：
ZHAO-WEN WANG
金额：
$ 30.6万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7783438
关键词：
Biological Assay Biotin Caenorhabditis elegans Cerebellar Ataxia Chimeric Proteins Chromosome Mapping Disease Disease Management Drosophila genus Engineering Epilepsy Erectile dysfunction Excretory function Fluorescence Functional disorder Future Genes Genetic Screening Genome Goals Haploidy Homologous Gene Human Hypertension Immunohistochemistry Interneurons Kidney Knowledge Label Mammals Membrane Mink Molecular Molecular Genetics Muscle Muscle Cells Mutation Names Nervous system structure Neuromuscular Junction Neurons Overactive Bladder Paroxysmal Dyskinesias Peptides Phenotype Physiological Presynaptic Terminals Property Protein Isoforms Proteins Research Screening procedure Site Surface Synapses System Testing Western Blotting Xenopus oocyte base density gain of function genetic regulatory protein glomerular filtration hearing impairment in vivo large-conductance calcium-activated potassium channels loss of function mutant neurotransmitter release novel postsynaptic presynaptic programs public health relevance research study voltage

项目摘要

DESCRIPTION (provided by applicant): BK channels are almost ubiquitously expressed and perform many important physiological functions. Dysfunction of the channel causes a variety of diseases, including epilepsy, progressive hearing loss, cerebellar ataxia, and hypertension. The function of BK channels depends on proper subcellular localization and interactions with auxiliary or regulatory proteins. However, the molecular basis of BK channel subcellular localization is unknown and only limited knowledge exists about BK channel auxiliary/regulatory proteins. The powerful molecular genetics of C. elegans is explored to identify proteins important to BK channel function or subcellular localization. In preliminary studies, mutants of three genes (named as bkip-1, bkip-2 and bkip-3) were isolated as suppressors of a lethargic phenotype caused by expressing a gain-of-function (gf) isoform of SLO-1, the C. elegans BK channel. Phenotypes of these mutants included increased neurotransmitter release (bkip-1) and SLO-1 mislocalization (bkip-2 and bkip-3). bkip-1 and bkip-2 were found to encode novel BK channel- interacting proteins whereas bkip-3 remains to be identified. BKIP-1 showed several effects on SLO-1 functional properties when analyzed in a heterologous expression system. This proposal is to test the hypotheses that the three BKIPs are important to SLO-1 function and/or subcellular localization in vivo and that there are other functionally related proteins in C. elegans. The specific aims of this proposal are: (1) determine how BKIP-1 regulates SLO-1 function; (2) determine how BKIP-2 and BKIP-3 control SLO-1 subcellular localization and/or function, and (3) isolate and identify additional mutants that suppress the lethargic phenotype caused by SLO-1(gf), which will be analyzed in future studies. The long-term goal is to elucidate the molecular basis of BK channel function and subcellular localization. PUBLIC HEALTH RELEVANCE: Mutations of the BK channel cause a variety of diseases, including epilepsy, hypertension, progressive hearing loss, cerebellar ataxia, overactive bladder, penile erectile dysfunction, impaired renal glomerular filtration and K+ excretion, and paroxysmal dyskinesia. The proposed research program may identify novel proteins that are important to BK channel function and/or subcellular localization in vivo. Such information is potentially of great value to understanding the molecular bases of BK channel-related diseases, and to identifying candidate pharmacological targets for the treatment and management of these diseases.