Cooperative and acute inhibition by multiple C-terminal motifs of L-type Ca²⁺ 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_V1.3 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 IQ_V (preIQ₃-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 (~65%) inhibited at the peak (full activation), but not later on (end-stage inactivation, ~300 ms). Meanwhile, CMI provides a new paradigm to develop Ca_V1 inhibitors, the therapeutic potential of which is implied by computational modeling of Ca_V1.3 dysregulations related to Parkinson's disease.