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 Ca2+-sensitive inactivation, its molecular mechanism is understood only in broad outline. We now demonstrate that Ca2+-dependent inactivation transpires by a Ca2+-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 Ca2+- 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.
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