Calcineurin mediates alpha-adrenergic stimulation of Na+,K(+)-ATPase activity in renal tubule cells.
The alpha-adrenergic agonist oxymetazoline increased Na+,K(+)-ATPase activity of single proximal convoluted tubules dissected from rat kidney. Activation of the enzyme by oxymetazoline was prevented by either the alpha 1-adrenergic antagonist prazosin or the alpha 2-adrenergic antagonist yohimbine and was mimicked by the calcium ionophore A23187. The effect of oxymetazoline on Na+,K(+)-ATPase activity was prevented by a specific peptide inhibitor of calcineurin, as well as by FK 506, an immunosuppressant agent known to inhibit calcineurin; these results indicate that the action of oxymetazoline is mediated via activation of calcineurin (a calcium/calmodulin-dependent protein phosphatase). Activation of the Na+,K(+)-ATPase by either oxymetazoline or A23187 was associated with a greater than 2-fold increase in its affinity for Na+. The results provide a biochemical mechanism by which norepinephrine, released from renal nerve terminals, stimulates Na+ retention.
Aperia
A
A
Department of Pediatrics, St. Göran's Children's Hospital, Karolinska Institutet, Stockholm, Sweden.
Ibarra
F
F
Svensson
L B
LB
Klee
C
C
Greengard
P
P
D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D007672:Kidney Cortex / Q000201:enzymology*; D007687:Kidney Tubules, Proximal / Q000201:enzymology*; D007700:Kinetics; D008954:Models, Biological; D010109:Oxymetazoline / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011090:Polyenes / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology*; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction; D020123:Sirolimus; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D016559:Tacrolimus / Q000494:pharmacology; D015016:Yohimbine / Q000494:pharmacology*
D002148:Calmodulin-Binding Proteins; D010455:Peptides; D011090:Polyenes; D011942:Receptors, Adrenergic, alpha; D015016:Yohimbine; D000001:Calcimycin; D010109:Oxymetazoline; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D000254:Sodium-Potassium-Exchanging ATPase; D020123:Sirolimus; D016559:Tacrolimus; D011224:Prazosin