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The voltage-dependent L-type Ca(2+) channel plays a key role in the spacial and temporal regulation of Ca(2+). 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 the Ca(2+)-dependent inactivation (CDI) of the Ca(2+) channel. We demonstrated that the CICR-dependent CDI of L-type Ca(2+) channels, under control of the privileged cross-signaling between L-type Ca(2+) channels and RyRs, plays 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. L-type Ca(2+) channels are modulated by the binding of Ca(2+) channel antagonists and agonists to the pore-forming alpha(1C) subunit. We identified Phe(1112) and Ser(1115) in the pore-forming IIIS5-S6 linker region of the alpha(1C) subunit as critical determinants of the binding of dihydropyridines (DHP). Interestingly, double mutant Ca(2+) channel (F1112A/S1115A) failed to discriminate between a DHP Ca(2+) channel agonist and antagonist stereoisomers. We proposed that Phe(1112) and Ser(1115) in the pore-forming IIIS5-S6 linker region is required for the stabilization of the Ca(2+) channel in the open state by Ca(2+) channel agonists and further proposed a novel model for the DHP-binding pocket of the alpha(1C) subunit. These integrative studies on the gating regulation of cardiac L-type Ca(2+) channels will provide the molecular basis for the pharmacology of Ca(2+) channel modulators.

Molecular and pharmacological bases for the gating regulation of L-type voltage-dependent Ca2+ channels.