Physiological modulation of inactivation in L‐type Ca2+ channels: one switch

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Abstract
The relative contributions of voltage- and Ca2+-dependent mechanisms of inactivation to the decay of L-type Ca2+ channel currents (ICaL) is an old story to which recent results have given an unexpected twist. In cardiac myocytes voltage-dependent inactivation (VDI) was thought to be slow and Ca2+-dependent inactivation (CDI) resulting from Ca2+ influx and Ca2+-induced Ca2+-release (CICR) from the sarcoplasmic reticulum provided an automatic negative feedback mechanism to limit Ca2+ entry and the contribution of ICaL to the cardiac action potential. Physiological modulation of ICaL by β-adrenergic and muscarinic agonists then involved essentially more or less of the same by enhancing or reducing Ca2+ channel activity, Ca2+ influx, sarcoplasmic reticulum load and thus CDI. Recent results on the other hand place VDI at the centre of the regulation of ICaL. Under basal conditions it has been found that depolarization increases the probability that an ion channel will show rapid VDI. This is prevented by β-adrenergic stimulation. Evidence also suggests that a channel which shows rapid VDI inactivates before CDI can become effective. Therefore the contributions of VDI and CDI to the decay of ICaL are determined by the turning on, by depolarization, and the turning off, by phosphorylation, of the mechanism of rapid VDI. The physiological implications of these ideas are that under basal conditions the contribution of ICaL to the action potential will be determined largely by voltage and by Ca2+ following β-adrenergic stimulation.