Transmission of information from cardiac dihydropyridine receptor to ryanodine receptor: evidence from BayK 8644 effects on resting Ca(2+) sparks.
Coupling between L-type Ca(2+) channels (dihydropyridine receptors, DHPRs) and ryanodine receptors (RyRs) plays a pivotal role in excitation-contraction (E-C) coupling in cardiac myocytes, and Ca(2+) influx is generally accepted as the trigger of sarcoplasmic reticulum (SR) Ca(2+) release. The L-type Ca(2+) channel agonist BayK 8644 (BayK) has also been reported to alter RyR gating via a functional linkage between DHPR and RyR, independent of Ca(2+) influx. Here, the effect of rapid BayK application on resting RyR gating in intact ferret ventricular myocytes was measured as Ca(2+) spark frequency (CaSpF) by confocal microscopy and fluo 3. BayK increased resting CaSpF by 401+/-15% within 10 seconds in Ca(2+)-free solution, and depolarization had no additional effect. The effect of BayK on CaSpF was dose-dependent, but even 50 nmol/L BayK induced a rapid 245+/-12% increase in CaSpF. Nifedipine (5 micromol/L) had no effect by itself on CaSpF, but it abolished the BayK effect (presumably by competitive inhibition at the DHPR). The nondihydropyridine Ca(2+) channel agonist FPL-64176 (1 micromol/L) did not alter CaSpF (despite rapid and potent enhancement of Ca(2+) current, I(Ca)). In striking contrast to the very rapid and depolarization-independent effect of BayK on CaSpF, BayK increased I(Ca) only slowly (tau=18 seconds), and the effect was greatly accelerated by depolarization. We conclude that in ferret ventricular myocytes, BayK effects on I(Ca) and CaSpF both require drug binding to the DHPR, but postreceptor pathways may diverge in transmission to the gating of the L-type Ca(2+) channel and RyR.
Katoh
H
H
Department of Physiology, Loyola University Chicago, Maywood, IL 60153, USA.
Schlotthauer
K
K
Bers
D M
DM
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000502:physiology*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000502:physiology*; D002478:Cells, Cultured; D005289:Ferrets; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles; D015640:Ion Channel Gating / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018613:Microscopy, Confocal; D009206:Myocardium / Q000166:cytology; D009543:Nifedipine / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology*
D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D011758:Pyrroles; D019837:Ryanodine Receptor Calcium Release Channel; C071658:FPL 64176; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009543:Nifedipine; D002118:Calcium