Ca(2+) entry into neurons is facilitated by cooperative gating of clustered CaV1.3 channels

Elife. 2016 May 17;5:e15744. doi: 10.7554/eLife.15744.

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.

Keywords: CaV1.3 channels; biophysics; calcium facilitation; hippocampal neurons; neuroscience; rat; structural biology.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium Channels / metabolism*
  • Calmodulin / metabolism
  • Electrophysiology
  • Hippocampus / cytology*
  • Neurons / metabolism*
  • Optical Imaging
  • Optogenetics
  • Protein Binding
  • Protein Interaction Mapping
  • Protein Multimerization*
  • Rats

Substances

  • Calcium Channels
  • Calmodulin
  • Cacna1d protein, rat
  • Calcium