Cyclic-AMP-dependent phosphorylation modulates the stereospecific activation of cardiac Ca channels by Bay K 8644.
Voltage-gated Ca channels have been reported to be regulated by membrane potential, phosphorylation and binding of specific agonists or antagonists such as dihydropyridines. We report here evidence that cyclic AMP (cAMP) modulates the activation of Ca-channel current by the dihydropyridine agonist Bay K 8644. Bay K 8644 (racemate) alone induces a primary voltage-dependent, potentiating effect on peak current amplitude and accelerates the current decay. In contrast, in the presence of cAMP activators, we observed a striking slowing of the decay in addition to the increase in peak current. The agonist (-)-Bay K 8644, but not the antagonist (+)-Bay K 8644, when applied in combination with cAMP, forskolin or isoproterenol, mimics the effect of the racemate. We have interpreted the results presented here in respect of a cAMP-dependent modulation of Bay K 8644 effects on cardiac Ca-channel currents. It may open the new perspective that dephosphorylated and phosphorylated Ca channels have distinct pharmacology.
Tiaho
F
F
Centre de Recherches de Biochimie Macromoléculaire, C.N.R.S. UPR 8402, I.N.S.E.R.M. U 249, Montpellier.
Richard
S
S
Lory
P
P
Nerbonne
J M
JM
Nargeot
J
J
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000493:pharmacokinetics; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology* / Q000502:physiology; D004338:Drug Combinations; D004553:Electric Conductivity / Q000187:drug effects / Q000502:physiology; D006321:Heart / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000166:cytology* / Q000648:ultrastructure; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats
D015220:Calcium Channels; D004338:Drug Combinations; D005576:Colforsin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000242:Cyclic AMP; D007545:Isoproterenol; D002118:Calcium