title: Cooperative and acute inhibition by multiple C-terminal motifs of L-type Ca2+channels.
abstract: 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.
authors.affiliation: X-Lab for Transmembrane Signaling Research, Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, China.
authors.forename: Nan
authors.identifier: 0000-0002-9606-4732
authors.initials: N
authors.lastname: Liu
authors.affiliation: X-Lab for Transmembrane Signaling Research, Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, China.
authors.forename: Yaxiong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: X-Lab for Transmembrane Signaling Research, Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Ge
authors.affiliation: X-Lab for Transmembrane Signaling Research, Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Physiology and Cellular Biophysics, Columbia University, New York, United States.
authors.forename: Henry M
authors.initials: HM
authors.lastname: Colecraft
authors.affiliation: X-Lab for Transmembrane Signaling Research, Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, China.|School of Life Sciences, Tsinghua University, Beijing, China.|IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China.
authors.forename: Xiaodong
authors.identifier: 0000-0002-3171-9611
authors.initials: X
authors.lastname: Liu
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002118:Calcium
keywords: Ca2+ channel inhibition; Ca2+ dependent inactivation; L-type Ca2+ channels; biophysics; calmodulin; distal carboxyl terminus; neuroscience; none; structural biology