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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.

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