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(Circulation Research. 2000;87:106.)
© 2000 American Heart Association, Inc.

Cellular Biology

Transmission of Information From Cardiac Dihydropyridine Receptor to Ryanodine Receptor

Evidence From BayK 8644 Effects on Resting Ca²⁺ Sparks

Hideki Katoh, Klaus Schlotthauer, Donald M. Bers

From the Department of Physiology, Loyola University Chicago, Maywood, Ill.

Correspondence to Donald M. Bers, PhD, Department of Physiology, Loyola University Medical School, 2160 S First Ave, Maywood, IL 60153. E-mail dbers{at}lumc.edu

Abstract—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 fluo 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 µmol/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 µmol/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 (=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. (Circ Res. 2000;87:106-111.)

Key Words: Ca²⁺ channel • sarcoplasmic reticulum • excitation-contraction coupling • confocal microscopy • FPL-64176

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