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Sodium Channel Biogenesis

钠通道生物发生

基本信息

批准号：
8517681
负责人：
Rebecca P Hughey
金额：
$ 30.66万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8517681
关键词：
Address Affect Aldosterone Alveolar Alveolus Anabolism Biogenesis Blood Pressure Cell membrane Cell surface Cleaved cell Cystic Fibrosis Cytoplasm Cytosol Distal Endoplasmic Reticulum Endoplasmic Reticulum Degradation Pathway Epithelium Extracellular Domain Extracellular Fluid Fingers Health Hypertension Hypotension Integral Membrane Protein Ion Channel Kidney Lesion Liquid substance Mediating Membrane Mutation Nephrons Nephrotic Syndrome Peptide Hydrolases Peptides Plasmin Polysaccharides Polyubiquitination Process Property Proteins Proteolysis Proteolytic Processing Quality Control Regulation Research Role Site Sodium Channel Structure Surface Syndrome System Testing Thumb structure Toxin Yeasts alpha helix epithelial Na+ channel extracellular gain of function mutation in vivo loss of function mutation multicatalytic endopeptidase complex palmitoylation prevent research study trafficking

项目摘要

DESCRIPTION (provided by applicant): Epithelial Na+ channel (ENaCs) are expressed in the aldosterone-sensitive distal nephron where they serve as the final site of renal Na+ reabsorption and have a key role in the regulation of extracellular fluid volume and blood pressure. ENaCs are also expressed throughout the airway and in alveoli, where they mediate Na+ reabsorption and have a critical role in regulating the volume of airway and alveolar fluids. Channel assembly appears to be an inefficient process, and quality control mechanisms within the ER have an important role in preventing exit of misfolded channel subunits from the ER while promoting the exit of properly assembled oligomeric channels for delivery to the cell surface. Channel subunits also undergo post- translational processing that includes cleavage by proteases. Proposed studies in Aim 1 will define quality control mechanisms within the ER that targets ENaC subunits for degradation. Proposed studies in Aim 2 will define the processing of ENaC subunits and regulation of channel activity by proteases. Proposed studies in Aim 3 will define the role of palmitoylation in the regulation of ENaC. These studies should generate new information regarding ENaC biogenesis and post-translational processing that provide additional levels of control of the cellular and surface pool of Na+ channels and of channel gating.

描述（由申请方提供）：上皮Na+通道（ENaCs）在醛固酮敏感性远端肾单位中表达，在那里它们作为肾Na+重吸收的最终位点，并在细胞外液量和血压的调节中起关键作用。ENaC也在整个气道和肺泡中表达，在那里它们介导Na+重吸收，并且在调节气道和肺泡流体的体积中具有关键作用。通道组装似乎是一个低效的过程，ER内的质量控制机制在防止错误折叠的通道亚基从ER中退出，同时促进正确组装的寡聚通道退出以递送至细胞表面方面具有重要作用。通道亚基还经历翻译后加工，包括被蛋白酶切割。目标1中提出的研究将定义ER中靶向ENaC亚基降解的质量控制机制。目标2中提出的研究将定义ENaC亚基的加工和蛋白酶对通道活性的调节。目标3中提出的研究将确定棕榈酰化在ENaC调节中的作用。这些研究应该产生新的信息ENaC生物发生和翻译后加工，提供额外的水平的控制细胞和表面池的Na+通道和通道门控。