Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 310, Issue 7, Pages E565-E571Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00360.2015
Keywords
gastrin; Na+, K+-ATPase; sodium transport; phosphatidylinositol 3-kinase; protein kinase C; calcium
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Funding
- National Institutes of Health [DK-039308, HL-092196]
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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 PKC alpha. 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, Go-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.
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