Cooperative and acute inhibition by multiple C-terminal motifs of L-type Ca2+ channels

Abstract

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, <i>e.g.</i>, 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.