GRK4 and D3R regulation of NHE3 and NCC expression

GRK4 和 D3R 对 NHE3 和 NCC 表达的调节

• 批准号: 7778674
• 负责人: Pedro A. Jose
• 金额: $ 43.54万
• 依托单位: UNIVERSITY OF VIRGINIA
• 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/7778674
• 关键词: Adenylate Cyclase; Angiotensin Receptor; Biological; Blood Pressure; Code; Complex; Conscious; DRD2 gene; Data; Deubiquitination; Development; Disease; Distal; Distal convoluted renal tubule structure; Dopamine; Dopamine Receptor; Duct (organ) structure; Electrolytes; Epithelial; Essential Hypertension; Excretory function; Family; Figs - dietary; Functional RNA; Functional disorder; G protein-coupled receptor kinase 4; G-Protein-Coupled Receptors; G-substrate; GTP-Binding Proteins; Gene Proteins; Gene Silencing; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Human; Hypertension; Hypotension; Impairment; Intake; Ion Transport; Kidney; Lead; Light; Limb structure; Link; Lithium; Mammals; Mediating; Molecular; Mus; Nephrons; Pathogenesis; Phenotype; Physiological; Potassium Channel; Proximal Kidney Tubules; Receptor Gene; Receptor, Angiotensin, Type 1; Regulation; Relative (related person); Renal function; Role; Site; Sodium; Sodium Channel; Sodium Chloride; Sodium-Hydrogen Antiporter; Testing; Thick; Transgenic Mice; Transplantation; Tubular formation; Ubiquitination; Variant; Water; Wild Type Mouse; base; blood pressure regulation; desensitization; dopamine D3 receptor; epithelial Na+ channel; familial hypertension; normotensive; overexpression; prevent; protein expression; receptor; receptor expression; receptor function; research study; salt sensitive; trafficking; ubiquitin-specific protease

lXhe long-term objective is to determine the interaction among the five dopamine receptors and other G protein-coupled receptors (GPCRs) in the regulation of renal electrolyte transport and blood pressure. The D3 dopamine receptor (D3R), by itself, or via its interaction, with other dopamine receptors (e.g., DIR) and other GPCRs (e.g., angiotensin type 1 receptor), regulates renal sodium transport and blood pressure. Deletion of the D3R gene (D3R-/-) results in saltsensitive hypertension that is associated with increased renal expression of sodium/hydrogen exchanger type 3 (NHE3[SLC9A3]), sodium chloride exchanger (NCC[SLC12A3]) and alpha subunit of the epithelial sodium channel (ENaC [SCNNl A ]). Preliminary data show that the D3R ubiquitinates NHE3 and that the ubiquitination of NHE3 is due to D3R-mediated inhibition of USP48, an ubiquitinase. The overall hypothesis of project 3 is that the hypertension in D3R-/- mice is caused by increased activity and expression of NHE3 and NCC; their increased expression is caused by decreased degradation due to deubiquitination by USP48. Specific aim 1 will test the hypothesis that impaired D3R function, because of decreased expression (D3-/-) or because of constitutive desensitization by human GRK4 gamma variants (e.g., GRK4 gammpl42V), results in increased renal expression of NHE3 and NCC when NaCI intake is normal and increased renal expression of NCC and ENaC when NaCI intake is increased. The impaired ability of D3-/-mice to excrete sodium contributes to the development of hypertension. Specific aim 2 will test the hypothesis that D3R inhibits USP4S activity, preventing the deubiquitination of NHE3 and NCC; this preserves their ubiquitination, resulting in increased degradation and therefore, decreased expression. Decreased expression of D3R, or impairment of D3R function by human GRK4gamma 142V, increases USP48 expression and activity, promotes the deubiquitination and prevents the degradation of NHE3 and NCC, thus, increasing their expression levels. Hypertension is a complex polygenic disease. However, based on our findings, GRK4 regulation of a limited number of GPCRs, and the downstream regulation of genes/proteins by GPCRs, e.g., D3R, makes a single gene, GRK4, a key contributor in the pathogenesis of essential hypertension.

lXhe的长期目标是确定五种多巴胺受体与其他G蛋白偶联的相互作用