Transmission of information from cardiac dihydropyridine receptor to ryanodine receptor -: Evidence from BayK 8644 effects on resting Ca2+ sparks

Coupling between L-type Ca2+ channels (dihydropyridine receptors, DHPRs) and ryanodine receptors (RyRs) plays a pivotal role in excitation-contraction (E-C) coupling in cardiac myocytes, and Ca2+ influx is generally accepted as the trigger of sarcoplasmic reticulum (SR) Ca2+ release. The L-type Ca2+ channel agonist BayK 8644 (BayK) has also been reported to alter RyR gating via a functional linkage between DHPR and RyR, independent of Ca2+ influx Here, the effect of rapid BayK application on resting RyR gating in intact ferret ventricular myocytes was measured as Ca2+ spark frequency (CaSpF) by confocal microscopy and flue 3. BayK increased resting CaSpF by 401+/-15% within 10 seconds in Ca2+-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 mu mol/L) had no effect by itself on CaSpF, but it abolished the BayK effect (presumably by competitive inhibition at the DHPR). The nondihydropyridine Ca2+ channel agonist FPL-64176 (1 mu mol/L) did not alter CaSpF (despite rapid and potent enhancement of Ca2+ 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 Ca2+ channel and RyR.