Inactivation of L-type calcium channels in cardiomyocytes.: Experimental and theoretical approaches

The L-type calcium current (I-Ca) plays an important role in excitation-contraction coupling of heart cells. It is critical for forming the major trigger for Ca2+-induced Ca2+ release from,the sarcoplasmic reticulum and hence its feedback regulation is of fundamental biological significance. The channel inactivation sharpens the kinetics and temporal precision of the Ca2+ signals so that it prevents longer-term increases in free intracellular Ca2+ concentration. Cardiac L-type Ca2+ channels are known to inactivate through voltage- and Ca2+-dependent mechanisms. Pure voltage-dependent inactivation has a much slower time course of development than Ca2+-dependent inactivation and plays minor role in inhibition of Ca2+ influx into the cell. The major determinant of the inactivation kinetics of Ca2+ current during depolarization is Ca2+-dependent mechanisms. Furthermore, it is possible to distinguish two phases in Ca2+-dependent inactivation of calcium current: a slow phase that depends on Ca2+ flow through the channels (Ca2+ current-dependent inactivation) and a fast one that depends on Ca2+ released from the sarcoplasmic reticulum (Ca2+ release-dependent inactivation). Although both Ca2+ released from the SR and Ca2+ permeating channels play a role, SR-released Ca2+ is the most effective inactivation mechanism in inhibition of Ca2+ entry through the channel.