Identification of the components controlling inactivation of voltage-gated Ca2+ channels

Ca2+-dependent inactivation (CDI) of L-type voltage-gated Ca2+ channels limits Ca2+ entry into neurons, thereby regulating numerous cellular events. Here we present the isolation and purification of the Ca2+-sensor complex, consisting of calmodulin (CaM) and part of the channel's pore-forming otic subunit, and demonstrate the Ca2+-dependent conformational shift that underlies inactivation. Dominant-negative CaM mutants that prevent CDI block the sensor's Ca2+-dependent conformational change. We show how IIe1654 in the CaM binding IQ motif of alpha(1c) forms the link between the Ca2+ sensor and the downstream inactivation machinery, using the alpha(1c) EF hand motif as a signal transducer to activate the putative pore-occluder, the alpha(1c) I-II intracellular linker.