MECHANISM OF CA2-SENSITIVE INACTIVATION OF L-TYPE CA2+ CHANNELS()

Many high threshold, voltage-gated Ca2+ channels, including the dihydr opyridine-sensitive class (L-type), inactivate in response not only to voltage, but also to entry of Ca2+. Despite the physiological importa nce of this Ca2+-sensitive inactivation, its molecular mechanism is un derstood 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 red uction of entry rate to the open state. A gating mechanism that explai ns this shift quantitatively and enables successful separation of Ca2- and voltage-sensitive forms of inactivation is deduced and tested. F inally, both calmodulin activation and channel (de)phosphorylation are excluded as significant signaling events underlying Ca2+-induced mode shifts, leaving direct binding of Ca2+ to the channel as a likely che mical initiation event for inactivation.