Calcium-mobilizing hormones and phorbol myristate acetate mediate heterologous desensitization of the hormone-sensitive hepatic Na+/K+ pump.
The Na+/K+ pump in rat hepatocytes is stimulated in response to Ca2+-mobilizing hormones such as [arginine]vasopressin (AVP), angiotensin II and adrenaline, as well as tumour promoters such as 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA). The ability of these agents to increase cellular contents of diacylglycerol and activate protein kinase C may be necessary to observe this response. In the present work, ouabain-sensitive 86Rb+ uptake was studied in isolated rat hepatocytes to help to explain why stimulation of the Na+/K+ pump by Ca2+-mobilizing hormones and tumour promoters is not temporally sustained relative to other hormone responses. A transient stimulation (3-4 min) of the Na+/K+ pump was observed in hepatocytes exposed to high (10 nM), but not low (0.1 nM), concentrations of AVP. Experiments with the Ca2+ chelator EGTA and the Na+ ionophore monensin indicate that the rapid secondary decrease in Na+/K+-pump activity which occurs after AVP stimulation is not due to changes in cytosolic Ca2+ and Na+ concentrations. When added after the stimulation and rapid decrease in Na+/K+-pump activity induced in hepatocytes by a high concentration of AVP, a second challenge with AVP or PMA failed to stimulate the pump. Similarly, previous exposure of hepatocytes to angiotensin, adrenaline or PMA attenuated the subsequent Na+/K+-pump responses to AVP and PMA. In contrast, previous exposure to AVP had no significant effect on subsequent stimulation of the Na+/K+-pump by monensin, glucagon, forskolin or 8-p-chlorophenylthio cyclic AMP. In addition, exposure to monensin had no effect on subsequent responses to AVP and PMA. These data indicate that high concentrations of Ca2+-mobilizing hormones and PMA result in heterologous desensitization of the hepatic Na+/K+ pump to subsequent stimulation by Ca2+-mobilizing hormones and PMA, but not by cyclic-AMP-dependent agonists or monensin.
Howard Hughes Medical Institute, Vanderbilt University School of Medicine, Nashville, TN 37232.
C J
CJ
Lynch
S B
SB
Bocckino
P F
PF
Blackmore
J H
JH
Exton
D000804:Angiotensin II / Q000493:pharmacokinetics; D000818:Animals; D001127:Arginine Vasopressin / Q000493:pharmacokinetics; D001693:Biological Transport, Active / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D004837:Epinephrine / Q000493:pharmacokinetics; D005934:Glucagon / Q000493:pharmacokinetics; D006728:Hormones / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008985:Monensin / Q000493:pharmacokinetics; D011188:Potassium / Q000378:metabolism*; D051381:Rats; D012964:Sodium / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000493:pharmacokinetics
D006728:Hormones; D000804:Angiotensin II; D001127:Arginine Vasopressin; D005934:Glucagon; D008985:Monensin; D012964:Sodium; D013755:Tetradecanoylphorbol Acetate; D011188:Potassium; D002118:Calcium; D004837:Epinephrine