TY - JOUR TI - Cooperative and acute inhibition by multiple C-terminal motifs of L-type Ca2+ channels AU - Liu, Nan AU - Yang, Yaxiong AU - Ge, Lin AU - Liu, Min AU - Colecraft, Henry M AU - Liu, Xiaodong A2 - Swartz, Kenton J VL - 6 PY - 2017 DA - 2017/01/06 SP - e21989 C1 - eLife 2017;6:e21989 DO - 10.7554/eLife.21989 UR - https://doi.org/10.7554/eLife.21989 AB - Inhibitions and antagonists of L-type Ca2+ channels are important to both research and therapeutics. Here, we report C-terminus mediated inhibition (CMI) for CaV1.3 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 (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 CaV1 inhibitors, the therapeutic potential of which is implied by computational modeling of CaV1.3 dysregulations related to Parkinson’s disease. KW - L-type Ca2+ channels KW - Ca2+ channel inhibition KW - calmodulin KW - distal carboxyl terminus KW - Ca2+ dependent inactivation JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -