Cooperative and acute inhibition by multiple C-terminal motifs of L-type Ca channels.

Inhibitions and antagonists of L-type Ca2+ channels are important to both research and therapeutics. Here, we report C-terminus mediated inhibition (CMI) for Ca(V)1.3 that multiple motifs coordinate to tune down Ca2+ current and Ca2+ influx toward the lower limits determined by end-stage CDI (Ca2+-dependent inactivation). Among IQV (preIQ(3)-IQ domain), PCRD and DCRD (proximal or distal C-terminal regulatory domain), spatial closeness of any two modules, e.g., by constitutive fusion, facilitates the trio to form the complex, compete against calmodulin, and alter the gating. Acute CMI by rapamycin-inducible heterodimerization helps reconcile the concurrent activation/inactivation attenuations to ensure Ca2+ influx is reduced, in that Ca2+ current activated by depolarization is potently (similar to 65%) inhibited at the peak (full activation), but not later on (end-stage inactivation, similar to 300 ms). Meanwhile, CMI provides a new paradigm to develop Ca(V)1 inhibitors, the therapeutic potential of which is implied by computational modeling of Ca(V)1.3 dysregulations related to Parkinsons disease.