Ca2+ inhibition of type III adenylyl cyclase in vivo.
Type III adenylyl cyclase is stimulated by beta-adrenergic agonists and glucagon in vitro and in vivo, but not by Ca2+ and calmodulin. However, the enzyme is stimulated by Ca2+ and calmodulin in vitro when it is concomitantly activated by the guanyl nucleotide stimulatory protein Gs (Choi, E. J., Xia, Z., and Storm, D. R. (1992a) Biochemistry 31, 6492-6498). Here, we examined regulation of type III adenylyl cyclase by Gs-coupled receptors and intracellular Ca2+ in vivo. Surprisingly, intracellular Ca2+ inhibited hormone-stimulated type III adenylyl cyclase activity. Submicromolar concentrations of intracellular free Ca2+, which stimulated type I adenylyl cyclase, inhibited glucagon- or isoproterenol-stimulated type III adenylyl cyclase. Inhibition of type III adenylyl cyclase by intracellular Ca2+ was not mediated by Gi, cAMP-dependent protein kinase, or protein kinase C. However, an inhibitor of CaM kinases antagonized Ca2+ inhibition of the enzyme, and coexpression of constitutively activated CaM kinase II completely inhibited isoproterenol-stimulated type III adenylyl cyclase activity. We propose that Ca2+ inhibition of type III adenylyl cyclase may serve as a regulatory mechanism to attenuate hormone-stimulated cAMP levels in some tissues.
Wayman
G A
GA
Department of Pharmacology, University of Washington, Seattle 98195, USA.
Impey
S
S
Storm
D R
DR
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives*; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002417:Cattle; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D004622:Embryo, Mammalian; D019204:GTP-Binding Proteins / Q000378:metabolism; D015723:Gene Library; D005934:Glucagon / Q000494:pharmacology*; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology; D007668:Kidney; D007700:Kinetics; D010879:Piperazines / Q000494:pharmacology; D018027:Receptors, Glucagon / Q000096:biosynthesis / Q000502:physiology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D014162:Transfection
D000067956:Adenylyl Cyclase Inhibitors; D007527:Isoenzymes; D007546:Isoquinolines; D010879:Piperazines; D018027:Receptors, Glucagon; D011994:Recombinant Proteins; D006165:Guanylyl Imidodiphosphate; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D005934:Glucagon; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D002118:Calcium