title: Ca(2+) entry into neurons is facilitated by cooperative gating of clustered CaV1.3 channels.
abstract: CaV1.3 channels regulate excitability in many neurons. As is the case for all voltage-gated channels, it is widely assumed that individual CaV1.3 channels behave independently with respect to voltage-activation, open probability, and facilitation. Here, we report the results of super-resolution imaging, optogenetic, and electrophysiological measurements that refute this long-held view. We found that the short channel isoform (CaV1.3S), but not the long (CaV1.3L), associates in functional clusters of two or more channels that open cooperatively, facilitating Ca(2+) influx. CaV1.3S channels are coupled via a C-terminus-to-C-terminus interaction that requires binding of the incoming Ca(2+) to calmodulin (CaM) and subsequent binding of CaM to the pre-IQ domain of the channels. Physically-coupled channels facilitate Ca(2+) currents as a consequence of their higher open probabilities, leading to increased firing rates in rat hippocampal neurons. We propose that cooperative gating of CaV1.3S channels represents a mechanism for the regulation of Ca(2+) signaling and electrical activity.
authors.affiliation: Department of Physiology and Membrane Biology, University of California, Davis, 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: Rose E
authors.initials: RE
authors.lastname: Dixon
authors.affiliation: Department of Physiology and Membrane Biology, University of California, Davis, United States.
authors.forename: Sendoa
authors.initials: S
authors.lastname: Tajada
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 Physiology and Membrane Biology, University of California, Davis, United States.
authors.forename: Luis F
authors.identifier: 0000-0002-4297-8029
authors.initials: LF
authors.lastname: Santana
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D004594:Electrophysiology; D006624:Hippocampus / Q000166:cytology*; D009474:Neurons / Q000378:metabolism*; D061848:Optical Imaging; D062308:Optogenetics; D011485:Protein Binding; D025941:Protein Interaction Mapping; D055503:Protein Multimerization; D051381:Rats
chemical_list: D015220:Calcium Channels; D002147:Calmodulin; C093712:Cacna1d protein, rat; D002118:Calcium
keywords: CaV1.3 channels; biophysics; calcium facilitation; hippocampal neurons; neuroscience; rat; structural biology