Mechanism of Ca(2+)-sensitive inactivation of L-type Ca2+ channels

Abstract

Many high threshold, voltage-gated Ca2+ channels, including the dihydropyridine-sensitive class (L-type), inactivate in response not only to voltage, but also to entry of Ca2+. Despite the physiological importance of this Ca(2+)-sensitive inactivation, its molecular mechanism is understood only in broad outline. We now demonstrate that Ca(2+)-dependent inactivation transpires by a Ca(2+)-induced shift of channel gating to a low open probability mode, distinguished by a more than 100-fold reduction of entry rate to the open state. A gating mechanism that explains this shift quantitatively and enables successful separation of Ca(2+)- and voltage-sensitive forms of inactivation is deduced and tested. Finally, both calmodulin activation and channel (de)phosphorylation are excluded as significant signaling events underlying Ca(2+)-induced mode shifts, leaving direct binding of Ca2+ to the channel as a likely chemical initiation event for inactivation.