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

• DOI: 10.7554/elife.21989
• Publication Date: 2017-01-06T13:04:21Z
• Authors: Nan Liu; Yaxiong Yang; Lin Ge; Min Liu; Henry M Colecraft; Xiaodong Liu
• Keywords: Ca2+ dependent inactivation; 0301 basic medicine; calmodulin; Calcium Channels, L-Type; QH301-705.5; Science; Q; R; Biophysics and Structural Biology; Calcium Channel Blockers; Ca2+ channel inhibition; 03 medical and health sciences; HEK293 Cells; distal carboxyl terminus; Medicine; Humans; Calcium; L-type Ca2+ channels; Biology (General)

Inhibitions and antagonists of L-type Ca2+ channels are important to both research therapeutics. Here, we report C-terminus mediated inhibition (CMI) for CaV1.3 that multiple motifs coordinate tune down current influx toward the lower limits determined by end-stage CDI (Ca2+-dependent inactivation). Among IQV (preIQ3-IQ domain), PCRD DCRD (proximal or distal C-terminal regulatory spatial closeness any two modules, e.g., constitutive fusion, facilitates trio form complex, compete against calmodulin, alter gating. Acute CMI rapamycin-inducible heterodimerization helps reconcile concurrent activation/inactivation attenuations ensure is reduced, in activated depolarization potently (~65%) inhibited at peak (full activation), but not later on (end-stage inactivation, ~300 ms). Meanwhile, provides a new paradigm develop CaV1 inhibitors, therapeutic potential which implied computational modeling dysregulations related Parkinson’s disease.