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The retinal L-type Ca2+ channel Cav1.4 is distinguished from all other members of the high voltage-activated (HVA) Ca2+ channel family by lacking Ca2+-calmodulin-dependent inactivation. In synaptic terminals of photoreceptors and bipolar cells, this feature is essential to translate graded membrane depolarizations into sustained Ca2+ influx and tonic glutamate release. The sequences conferring Ca2+-dependent inactivation (CDI) are conserved throughout the HVA calcium channel family, raising the question of how Cav1.4 manages to switch off CDI. Here, we identify an autoinhibitory domain in the distal C terminus of Cav1.4 that serves to abolish CDI. We show that this domain (ICDI, inhibitor of CDI) uncouples the molecular machinery conferring CDI from the inactivation gate by binding to the EF hand motif in the proximal C terminus. Deletion of ICDI completely restores Ca2+-calmodulin-mediated CDI in Cav1.4. CDI can be switched off again in the truncated Cav1.4 channel by coexpression of ICDI, indicating that ICDI works as an autonomous unit. Furthermore, we show that in the Cav1.2 l-type Ca2+-channel replacement of the distal C terminus by the corresponding sequence of Cav1.4 is sufficient to block CDI. This finding suggests that autoinhibition of CDI can be introduced principally into other Ca2+ channel types. Our data provide a previously undescribed perspective on the regulation of HVA calcium channels by Ca2+.

Switching off calcium-dependent inactivation in l -type calcium channels by an autoinhibitory domain