The Biology of NBCe1 in Health and Disease

NBCe1 在健康和疾病中的生物学

• 批准号: 8779719
• 负责人: IRA KURTZ
• 金额: $ 33.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8779719
• 关键词: Acid-Base Equilibrium; Acids; Affect; Anions; Apical; Area; Bicarbonates; Binding; Binding Sites; Biology; Carbonates; Carrier Proteins; Cell membrane; Cells; Cellular biology; Chemistry; Clinical; Coupled; Data; Disease; Distal renal tubular acidosis Type 1; Equilibrium; Family; Food; Funding; Genes; Grant; Health; Hereditary Disease; Human; Ions; Kidney; Location; Maintenance; Mammalian Cell; Mammals; Mediating; Membrane; Membrane Transport Proteins; Modeling; Molecular; Mus; Mutate; Mutation; NBL1 gene; Nature; Nitrates; Organ; Pathway interactions; Phase; Physiological; Play; Property; Protocols documentation; Proximal Kidney Tubules; Proximal Renal Tubular Acidosis; Publishing; Renal tubular acidosis; Research Personnel; Role; Sodium; Structure; Tissues; absorption; base; improved; man; member; novel; oxidation; research study; success

DESCRIPTION (provided by applicant): The SLC4 family of membrane transporters mediate Cl--HCO3- and Na+-driven Cl--HCO3- exchange, and Na+- HCO3- cotransport (electrogenic, electroneutral). The importance of these transporters in mammalian cell biology is highlighted by the phenotypic abnormalities resulting from spontaneous SLC4 mutations in humans and targeted deletions in mice. Abnormalities in either the function and/or plasma membrane expression of certain members of the SLC4 family are the cause of various genetic diseases in man. Of the known SLC4 genes, SLC4A4 (NBCe1) and SLC4A1 (AE1) play key roles in mediating renal bicarbonate absorption, and the maintenance of systemic and intracellular acid-base balance. Mutations in NBCe1 impair both proximal tubule and extrarenal acid-base transport. In preliminary experiments, we have begun to examine the structural basis for the functional properties of NBCe1 and have made several novel discoveries that form the background for this proposal. Preliminary studies of the anion binding machinery of NBCe1 have led to the novel finding that it functions as both an electrogenic Na+-CO32- cotransporter and an electroneutral Na+-NO3- cotransporter. Mutations in NBCe1 that cause renal tubular acidosis also inhibit NO3- transport. Based on these new findings, NBCe1 must now be considered to be a bi-functional transporter that mediates carbonate and nitrate transport in the proximal tubule, and potentially in extrarenal tissues where it is expressed. Given our findings that NBCe1 transports Na+-CO32- and Na+-NO3-, the role of the kidney and the proximal tubule in inter-organ NO3- cycling and whole body NO3- balance becomes particularly relevant both from a physiologic and clinical standpoint. The proposal will characterize the architectural basis for the function of NBCe1 as both an electrogenic Na+-CO32- cotransporter and an electroneutral Na+-NO3- cotransporter, the perturbation of these functional properties in disease, and the role of NBCe1 and the proximal tubule in NO3- transport.

描述（由申请人提供）：SLC4 膜转运蛋白家族介导 Cl--HCO3- 和 Na+ 驱动的 Cl--HCO3- 交换，以及 Na+- HCO3- 共转运（生电、电中性）。人类自发 SLC4 突变和小鼠定向缺失导致的表型异常凸显了这些转运蛋白在哺乳动物细胞生物学中的重要性。 SLC4家族某些成员的功能和/或质膜表达异常是人类多种遗传疾病的原因。在已知的 SLC4 基因中，SLC4A4 (NBCe1) 和 SLC4A1 (AE1) 在介导肾脏碳酸氢盐吸收以及维持全身和细胞内酸碱平衡方面发挥着关键作用。 NBCe1 突变会损害近端小管和肾外酸碱转运。在初步实验中，我们已经开始研究 NBCe1 功能特性的结构基础，并取得了一些新的发现，这些发现构成了本提案的背景。对 NBCe1 阴离子结合机制的初步研究得出了新的发现，即它既可作为生电 Na+-CO32- 协同转运蛋白，又可作为电中性 Na+-NO3- 协同转运蛋白。引起肾小管酸中毒的 NBCe1 突变也会抑制 NO3- 转运。基于这些新发现，NBCe1 现在必须被认为是一种双功能转运蛋白，可介导近端小管中的碳酸盐和硝酸盐转运，并可能在其表达的肾外组织中介导。鉴于我们的发现 NBCe1 转运 Na+-CO32- 和 Na+-NO3-，从生理和临床角度来看，肾脏和近端小管在器官间 NO3- 循环和全身 NO3- 平衡中的作用变得特别相关。该提案将描述 NBCe1 作为生电 Na+-CO32- 协同转运蛋白和电中性 Na+-NO3- 协同转运蛋白功能的结构基础、这些功能特性在疾病中的扰动，以及 NBCe1 和近端小管在 NO3 中的作用- 运输。