Calcium entry via L-type calcium channels acts as a negative regulator of adenylyl cyclase activity and cyclic AMP levels in cardiac myocytes.
It is well established that the inotropic effect of beta-adrenergic agonists is mediated by the stimulation of adenylyl cyclase activity and the subsequent phosphorylation of specific proteins by cAMP-dependent protein kinase. The L-type calcium channel is believed to be one of the proteins phosphorylated; the phosphorylation of calcium channels is believed to increase calcium entry into myocytes, which is, at least in part, responsible for the positive inotropic effect. The present studies show that the cAMP-elevating effect of isoproterenol is increased as extracellular calcium is lowered and that calcium channel blockers potentiate the cAMP-elevating effect of isoproterenol in the presence in extracellular calcium. This effect is not dependent on effects on cAMP catabolism and is not specific for beta-adrenergic receptors, because the cAMP-elevating effect of forskolin is similarly affected. Measurements of adenylyl cyclase activity in cardiac membranes show that submicromolar Ca2+ concentrations directly inhibit adenylyl cyclase activity. These results demonstrate that increased entry of Ca2+ via L-type calcium channels in response to beta-adrenergic receptor stimulation acts as a negative regulator of the effect of beta receptor stimulation on adenylyl cyclase activity.
Yu
H J
HJ
Department of Pharmacology, University of Illinois at Chicago 60612.
Ma
H
H
Green
R D
RD
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D002642:Chick Embryo; D000242:Cyclic AMP / Q000378:metabolism*; D003864:Depression, Chemical; D015536:Down-Regulation; D004357:Drug Synergism; D006321:Heart / Q000187:drug effects / Q000502:physiology; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007700:Kinetics; D020105:Milrinone; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D020889:Rolipram
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D011760:Pyrrolidinones; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D020105:Milrinone; D020889:Rolipram; D007545:Isoproterenol; D002118:Calcium