L-type Ca2+ channels serve as a sensor of the SR Ca2+ for tuning the efficacy of Ca2+-induced Ca2+ release in rat ventricular myocytes

Abstract

In cardiac excitation-contraction coupling, Ca(2+)-induced Ca(2+) release (CICR) from ryanodine receptors (RyRs), triggered by Ca(2+) entry through the nearby L-type Ca(2+) channel, induces Ca(2+)-dependent inactivation (CDI) of the Ca(2+) channel. Aiming at elucidating the physiological role of CDI produced by CICR (CICR-dependent CDI), we investigated the contribution of the CICR-dependent CDI to action potential (AP) waveform and the amount of Ca(2+)-influx through Ca(2+) channels during AP in rat ventricular myocytes. The elimination of the CICR-dependent CDI, by depletion of the SR Ca(2+) with thapsigargin, significantly prolonged AP duration (APD). APD changed in parallel with the magnitude of CICR during the recovery of the SR Ca(2+) content after transient depletion by caffeine. Such CICR-dependent change of APD persisted under the highly Ca(2+) buffered condition where the Ca(2+) signalling was restricted to nanoscale domains. Blockers of the Ca(2+)-dependent Cl(−) channel or the BK channel did not affect AP waveform. The amount of Ca(2+)-influx through Ca(2+) channels during the SR-depleted type AP waveform, measured in the SR-depleted myocyte, was increased by 40% over that during the SR-intact type AP waveform measured in the SR-intact myocyte. The protein kinase A stimulation further enhanced the Ca(2+)-influx during AP under the SR-depleted condition to 70% of that under the SR-intact condition. These results indicate that the CICR-dependent CDI of L-type Ca(2+) channels, under control of the privileged cross-signalling between L-type Ca(2+) channels and RyRs, play important roles for monitoring and tuning the SR Ca(2+) content via changes of AP waveform and the amount of Ca(2+)-influx during AP in ventricular myocytes.