Cooperative and acute inhibition by multiple C-terminal motifs of L-type Ca(2+) channels

Inhibitions and antagonists of L-type Ca(2+) 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 Ca(2+) current and Ca(2+) influx toward the lower limits determined by end-stage CDI (Ca(2+)-dependent inactivation). Among IQ(V) (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 Ca(2+) influx is reduced, in that Ca(2+) 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(V)1 inhibitors, the therapeutic potential of which is implied by computational modeling of Ca(V)1.3 dysregulations related to Parkinson’s disease. DOI: http://dx.doi.org/10.7554/eLife.21989.001