title: Graded Ca²⁺/calmodulin-dependent coupling of voltage-gated CaV1.2 channels.
abstract: In the heart, reliable activation of Ca(2+) release from the sarcoplasmic reticulum during the plateau of the ventricular action potential requires synchronous opening of multiple CaV1.2 channels. Yet the mechanisms that coordinate this simultaneous opening during every heartbeat are unclear. Here, we demonstrate that CaV1.2 channels form clusters that undergo dynamic, reciprocal, allosteric interactions. This 'functional coupling' facilitates Ca(2+) influx by increasing activation of adjoined channels and occurs through C-terminal-to-C-terminal interactions. These interactions are initiated by binding of incoming Ca(2+) to calmodulin (CaM) and proceed through Ca(2+)/CaM binding to the CaV1.2 pre-IQ domain. Coupling fades as [Ca(2+)]i decreases, but persists longer than the current that evoked it, providing evidence for 'molecular memory'. Our findings suggest a model for CaV1.2 channel gating and Ca(2+)-influx amplification that unifies diverse observations about Ca(2+) signaling in the heart, and challenges the long-held view that voltage-gated channels open and close independently.
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, United States.
authors.forename: Rose E
authors.initials: RE
authors.lastname: Dixon
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, United States.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Moreno
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, United States.
authors.forename: Can
authors.initials: C
authors.lastname: Yuan
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, United States.
authors.forename: Ximena
authors.initials: X
authors.lastname: Opitz-Araya
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, United States.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Binder
authors.affiliation: Department of Pharmacology, University of California, Davis, Davis, United States.
authors.forename: Manuel F
authors.initials: MF
authors.lastname: Navedo
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, United States.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Santana
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D015640:Ion Channel Gating; D008390:Markov Chains; D008564:Membrane Potentials; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D011817:Rabbits
chemical_list: D020746:Calcium Channels, L-Type; D002147:Calmodulin; C419385:L-type calcium channel alpha(1C); D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
keywords: EC coupling; biophysics; calcium sparklets; calmodulin; coupled gating; mouse; structural biology; voltage-gated calcium channels