Sodium Channel Biogenesis

钠通道生物发生

• 批准号: 7587721
• 负责人: Rebecca P Hughey
• 金额: $ 35.77万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7587721
• 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; 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; public health relevance; research study; trafficking

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. PUBLIC HEALTH RELEVANCE: Epithelial Na+ channels have key roles in the regulation of extracellular fluid volume, blood pressure and the volume of airway and alveolar fluids. Our proposed studies will address cellular mechanisms that are involved in the biogenesis and post-translational processing of Na+ channels. Enhanced ENaC proteolysis contributes to the increase in channel activity observed in Liddle's syndrome and in cystic fibrosis, and may contribute to the increase in Na+ retention that occurs in nephrotic syndrome. At a basic level, our studies are relevant to understanding the process of ER associated degradation (ERAD). Our proposed studies are particularly relevant to oligomeric integral membrane proteins, as their cellular requirements for ERAD may evolve upon the acquisition of their quaternary structure.

描述（由申请人提供）：上皮Na+通道（ENaCs）在醛固酮敏感的远端肾单位中表达，在那里它们是肾Na+重吸收的最终位点，在调节细胞外液容量和血压中起关键作用。ENaCs也在整个气道和肺泡中表达，介导Na+再吸收，并在调节气道和肺泡液的体积中起关键作用。通道组装似乎是一个低效的过程，内质网内的质量控制机制在防止错误折叠的通道亚基从内质网退出，同时促进正确组装的低聚通道退出并递送到细胞表面方面发挥着重要作用。通道亚基也经历翻译后加工，包括蛋白酶的裂解。Aim 1中提出的研究将定义内质网中针对ENaC亚基降解的质量控制机制。Aim 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。Aim 3中提出的研究将确定棕榈酰化在ENaC调节中的作用。这些研究应该会产生关于ENaC生物发生和翻译后处理的新信息，从而提供对Na+通道和通道门控的细胞和表面池的额外控制。公共卫生相关性：上皮Na+通道在调节细胞外液容量、血压以及气道和肺泡液容量方面发挥关键作用。我们提出的研究将涉及Na+通道的生物发生和翻译后加工的细胞机制。ENaC蛋白水解的增强有助于Liddle综合征和囊性纤维化中通道活性的增加，并可能导致肾病综合征中Na+潴留的增加。在基本水平上，我们的研究与理解内质网相关降解（ERAD）的过程有关。我们提出的研究与低聚整体膜蛋白特别相关，因为它们对ERAD的细胞需求可能随着其四级结构的获得而进化。