title: Gastrin decreases Na+,K+-ATPase activity via a PI 3-kinase- and PKC-dependent pathway in human renal proximal tubule cells.
abstract: The natriuretic effect of gastrin suggests a role in the coordinated regulation of sodium balance by the gastrointestinal tract and the kidney. The renal molecular targets and signal transduction pathways for such an effect of gastrin are largely unknown. Recently, we reported that gastrin induces NHE3 phosphorylation and internalization via phosphatidylinositol (PI) 3-kinase and PKCα. In this study, we show that gastrin induced the phosphorylation of human Na(+),K(+)-ATPase at serine 16, resulting in its endocytosis via Rab5 and Rab7 endosomes. The gastrin-stimulated phosphorylation of Na(+),K(+)-ATPase was dependent on PI 3-kinase because the phosphorylation was blocked by the PI 3-kinase inhibitor wortmannin. The phosphorylation of Na(+),K(+)-ATPase was also blocked by chelerythrine, a pan-PKC inhibitor, Gö-6976, a conventional PKC (cPKC) inhibitor, and BAPTA-AM, an intracellular calcium chelator, suggesting the importance of cPKC and intracellular calcium in the gastrin signaling pathway. The gastrin-mediated phosphorylation of Na(+),K(+)-ATPase was also inhibited by U-73122, a phospholipase C (PLC) inhibitor. These results suggest that gastrin regulates sodium hydrogen exchanger and pump in renal proximal tubule cells at the apical and basolateral membranes.
authors.affiliation: Center for Molecular Physiology Research, Children's Research Institute, Children's National Medical Center, Washington, DC;
authors.forename: Tianbing
authors.initials: T
authors.lastname: Liu
authors.affiliation: Departments of Medicine and Physiology, University of Maryland School of Medicine, Baltimore, Maryland; Division of Renal Diseases and Hypertension, Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC; and.
authors.forename: Prasad R
authors.initials: PR
authors.lastname: Konkalmatt
authors.affiliation: Center for Molecular Physiology Research, Children's Research Institute, Children's National Medical Center, Washington, DC; Departments of Medicine and Physiology, University of Maryland School of Medicine, Baltimore, Maryland;
authors.forename: Yu
authors.initials: Y
authors.lastname: Yang
authors.affiliation: pjose@mfa.gwu.edu.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Jose
mesh_terms: D002118:Calcium / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D011992:Endosomes / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D005755:Gastrins / Q000494:pharmacology*; D006728:Hormones / Q000494:pharmacology*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D017923:Sodium-Hydrogen Exchangers / Q000187:drug effects* / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects* / Q000378:metabolism; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D002227:Carbazoles; D004791:Enzyme Inhibitors; D004963:Estrenes; D005755:Gastrins; D006728:Hormones; D011760:Pyrrolidinones; D017923:Sodium-Hydrogen Exchangers; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C081021:Go 6976; D058539:Phosphatidylinositol 3-Kinase; D011493:Protein Kinase C; D010738:Type C Phospholipases; C427755:RAB5C protein, human; D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium
keywords: Na+,K+-ATPase; calcium; gastrin; phosphatidylinositol 3-kinase; protein kinase C; sodium transport