Carboxyl Terminus as a Key Regulator of Gating and Signaling of L-Type Calcium Channels

Abstract

L-type calcium channels (CaV1) play vital roles in critical biological processes including calcium dynamics and gene regulation, where the carboxyl terminus of CaV1 gets closely involved. In this presentation, we are introducing some of the recent progress and findings about C-tail's roles in CaV1 gating and signaling. First, we report C-terminus mediated inhibition (CMI) for CaV1.3 that multiple motifs coordinate to compete calmodulin (CaM) off the channel, and tune down Ca2+ current and Ca2+ influx toward the lower limits determined by end-stage CDI (Ca2+-dependent inactivation). Acute CMI by rapamycin-inducible heterodimerization helps reconcile the concurrent activation/inactivation attenuations to ensure CMI as a new modality of channel inhibition (Liu N, et al., eLife, 2017). Data suggest that CMI could also profoundly affect the downstream Ca2+ signaling especially the CaV1-dependent gene regulation. Such importance of C-tail is in part demonstrated by the work dealing with the side-effects of CaM-based GCaMP, one of the most popular types of Ca2+ probes. We unveil the intrinsic problem prevailing over different versions and applications, that GCaMP acts as impaired CaM of apo and Ca2+ forms both critical to C-tail functions in CaV1, resulting into distorted Ca2+ dynamics and altered gene expression. We then design and implement GCaMP-X, which successfully resolves the problems of detrimental nuclear accumulation, acute and chronic Ca2+ dysregulation, and abnormal cell morphogenesis. The interplays between the C-terminus and signaling proteins well demonstrate the ultimate and synergistic tasks of CaV1 complex: to deliver Ca2+ of appropriate spatiotemporal patterns (gating) to the right listeners and actuators (signaling).