Evidence for participation of calcineurin in potentiation of agonist-stimulated cyclic AMP formation by the calcium-mobilizing hormone, angiotensin II.
Angiotensin II (AII) receptors are known to interact with two distinct guanine nucleotide binding proteins, Gq/11 and Gi, in rat adrenal glomerulosa cells to activate phospholipase C and to inhibit adenylate cyclase, respectively. However, in cultured bovine glomerulosa cells AII potentiates rather than inhibits the stimulatory effect of adrenocorticotropin (ACTH) on cAMP levels. This effect of AII was partially mimicked by phorbol 12-myristate 13-acetate (PMA) and was partially inhibited by staurosporine or depletion of protein kinase C but was unaffected by pertussis toxin treatment. No potentiation was detectable in disrupted cells or in membrane preparations. In intact glomerulosa cells, treatment with cyclosporin A or FK506 completely inhibited AII- or PMA-induced potentiation of cAMP production without affecting the response to ACTH. In COS-7 cells transfected with the rat AT1 receptor, AII caused 2-3-fold enhancement of the ACTH-induced cAMP response, an effect that was partially reproduced by PMA. These potentiating actions of AII and PMA were prevented by preincubation with cyclosporin A or FK506, and the latter effect was abolished by rapamycin. These results implicate the Ca2+- and calmodulin-dependent protein phosphatase, calcineurin, in AII-induced enhancement of adenylate cyclase activity in both adrenal glomerulosa and transfected COS-7 cells. The finding that AII enhances ACTH-stimulated production of cAMP by a second messenger-mediated mechanism that involves the participation of calcineurin reveals an additional mode of cross-talk between pathways activated by Ca(2+)-mobilizing and cAMP-generating receptors.
Baukal
A J
AJ
Endocrinology and Reproduction Research Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892.
Hunyady
L
L
Catt
K J
KJ
Balla
T
T
D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D019703:Calcineurin; D002118:Calcium / Q000502:physiology*; D002148:Calmodulin-Binding Proteins / Q000502:physiology*; D002417:Cattle; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis*; D004357:Drug Synergism; D019204:GTP-Binding Proteins / Q000502:physiology; D010749:Phosphoprotein Phosphatases / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology; D011945:Receptors, Angiotensin / Q000032:analysis
D002148:Calmodulin-Binding Proteins; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D000324:Adrenocorticotropic Hormone; D000242:Cyclic AMP; D011493:Protein Kinase C; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D019204:GTP-Binding Proteins; D002118:Calcium