Calicum, MARCKS, and PIP2 regulation of ENaC

ENaC 的钙、MARCKS 和 PIP2 调节

• 批准号: 8700958
• 负责人: Abdel Ayube Alli
• 金额: $ 13.37万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700958
• 关键词: Actins; Adaptor Signaling Protein; Alveolar; Amiloride; Animals; Apical; Binding; Calcium; Calcium Binding; Calmodulin; Calpain; Carrier Proteins; Cell membrane; Cells; Cleaved cell; Colon; Congestive Heart Failure; Cytoplasm; Cytoskeleton; Disease; Distal; Embryo; End stage renal failure; Epithelial; Epithelial Cells; Essential Hypertension; Etiology; F-Actin; Fluid Balance; Homeostasis; Hypertension; Hypotension; Inherited; Injection of therapeutic agent; Kidney; Knock-out; Knockout Mice; Laboratories; Lead; Learning; Liquid substance; Lung; Mediating; Membrane; Membrane Lipids; Membrane Proteins; Methods; Modeling; Molecular; Mus; Mutation; Names; Nephrons; PKC Phosphorylation Site; Peptide Hydrolases; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phosphorylation; Post-Translational Protein Processing; Probability; Protein Binding; Protein Kinase C; Proteolysis; Public Health; Regulation; Reporting; Risk Factors; Role; Sodium; Sodium Channel; Stroke; System; Testing; apical membrane; aquaporin-2; blood pressure regulation; embryonic stem cell; epithelial Na+ channel; epithelial amiloride-sensitive sodium channel; extracellular; in vivo; inorganic phosphate; knock-down; myristoylated alanine-rich C kinase substrate; promoter; public health relevance; recombinase; small hairpin RNA; success; tissue culture

Abstract Hypertension is a major public health concern because it is an important risk factor for many other diseases including congestive heart failure, stroke, and end-stage renal disease. The constitutive activation of epithelial sodium channels (ENaC) leads to severe hypertension, while subtle stimulation of ENaC may contribute to essential hypertension. Therefore, understanding the regulation of ENaC is important to understand the etiology of hypertension. Our laboratory was among the first to show that ENaC activity requires binding of phosphatidylinositol bis-phosphate (PIP2) to the amino terminal domain of ENaC subunits. We used a tissue culture model of distal nephron sodium transport and we showed that the PIP2 dependent regulation of ENaC is mediated by an adaptor protein, myristoylated alanine-rich C kinase substrate (MARCKS), that binds PIP2 and increases the local concentration of PIP2 near ENaC and, thereby, activates ENaC. The myristoylated amino terminal domain and the basic effector domain of MARCKS both contribute to its function at the apical plasma membrane. The function of MARCKS can be regulated by posttranslational modifications, association with calcium/calmodulin, and proteolysis so that regulation of MARCKS is also important for regulating ENaC. The aims of this project are to show how MARCKS regulates ENaC in vivo and identify the molecular mechanisms that regulate MARCKS activity at the apical membrane of renal epithelial cells.

摘要