Mechanisms of inactivation of L-type calcium channels in human atrial myocytes

We used whole cell patch-clamp and microfluorimetric (indo 1) techniques to measure Ca²⁺ current through L-type Ca²⁺ channels (I(Ca)) and Ca²⁺ transients in human atrial myocytes. During 1-s depolarizing pulses, I(Ca) inactivation was biexponential. The rate of rapid inactivation was slowed by ryanodine and was correlated with the rate of rise of cytoplasmic free Ca²⁺ concentration (r = 0.80, P < 0.01). Slower-phase I(Ca) inactivation was not affected by ryanodine but was accelerated by increasing the availability of Ca²⁺ to permeate the Ca²⁺ channel. Thus Ca²⁺ released from the sarcoplasmic reticulum (SR) was responsible for most I(Ca) inactivation during the first 50 ms of a depolarization to 0 mV, and thereafter inactivation by Ca²⁺ permeating the channel predominated. Pure voltage- dependent inactivation had a much slower time course of development (τ > 2s) and played a smaller role than Ca²⁺-dependent mechanisms over a duration comparable to that of an action potential. We conclude that human atrial myocytes show both voltage- and Ca²⁺-dependent I(Ca) inactivation, that Ca²⁺-dependent mechanisms predominate over the time course of an action potential, and that although both Ca²⁺ released from the SR and Ca²⁺ permeating Ca²⁺ channels play a role, SR-released Ca²⁺ is particularly important in early, rapid I(Ca) inactivation, whereas Ca²⁺ permeating Ca²⁺ channels is more important in the slower phase of Ca²⁺-dependent inactivation.