Modeling Mechanisms of Cardiac L-Type Ca2+ Channel Regulation: Interactions of Voltage, Ca2+, and Isoflurane

Abstract

Calcium influx via L-type Ca2+ channel (LCC) in cardiomyocytes (CM) is regulated by both voltage-dependent and Ca2+-dependent inactivation (VDI, CDI) mechanisms, which are not well understood. Also, how isoflurane (ISO), a volatile anesthetic cardioprotective agent, exerts negative inotropic effect on CM by modulating LCC, possibly VDI and/or CDI, is lacking. We extended a previously developed Markov model of LCC to investigate these different regulation mechanisms, based on diverse published kinetic data on whole-cell patch-clamp of ventricular myocytes, with different charge carriers, ISO concentrations, and voltage-clamp protocols. It is understood experimentally that the accumulated Ca2+ in the vicinity (nanodomain) of LCC Ca2+ sensors, as Ca2+ passes through the channel, is responsible for most of CDI, independent of Ca2+ in the dyadic space (microdomain) due to Ca2+ induced Ca2+ release (CICR). The previous LCC model, which includes distinct voltage and Ca2+ modes of LCC, cannot fully describe CDI mechanism. Interestingly, it is also observed that ISO dose-dependently inhibits LCC and its steady state inactivation/availability. To quantify these mechanisms, we extended the previous LCC model to incorporate possible interactions of ISO with the two LCC modes. We also incorporated a Ca2+ nanodomain in the vicinity of LCC Ca2+ sensors and simulated Ca2+ dynamics in this region to quantify the native role of Ca2+ entry on CDI of LCC, independent of CICR. The extended LCC model systematically reproduces various aspects of LCC regulation underlying VDI and CDI, and their regulation by ISO, in addition to providing contributions of Ca2+ nanodomain for CDI, independent of CICR. The LCC model also predicts that the depressant action of ISO on LCC is dependent on ISO interactions with the open and inactivated states of LCC.