Regulation of Na+, K+-ATPase by the endogenous sodium transport inhibitor from hypothalamus.
We characterized the effect of a small, nonpeptidic molecule isolated from bovine hypothalamus on mammalian Na+, K+-adenosine triphosphatase (ATPase). This hypothalamic factor has been shown to inhibit ATPase activity of purified dog kidney enzyme reversibly with high affinity. This report reviews the mechanism of inhibition. Hypothalamic factor inhibits Na+, K+-ATPase only from the extracellular surface. It prevents the phosphorylation from magnesium and inorganic phosphate of the active site aspartate residue of Na+, K+-ATPase and stabilizes the enzyme in an E2 conformation, preventing a sodium-induced shift from E2 to E1. Binding and dissociation reactions of hypothalamic factor in cultured renal tubular epithelial cells show a time frame different from that in isolated membranes and consistent with physiological relevance. A possible mechanism for the physiological regulation of Na+, K+-ATPase, including a cycle of binding and rapid dissociation in intact renal tubular cells, is discussed.
Haupert
G T
GT
Renal Unit, Massachusetts General Hospital, Boston 02114.
D000818:Animals; D001665:Binding Sites; D001693:Biological Transport, Active / Q000187:drug effects; D002417:Cattle; D002460:Cell Line; D004285:Dogs; D004789:Enzyme Activation; D004848:Epithelium / Q000201:enzymology; D007031:Hypothalamus / Q000032:analysis*; D007687:Kidney Tubules, Proximal / Q000166:cytology; D008954:Models, Biological; D010042:Ouabain / Q000494:pharmacology; D010455:Peptides / Q000302:isolation & purification / Q000494:pharmacology*; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism*
D010455:Peptides; C029311:serum sodium transport inhibitor; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase