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Open Access Publications from the University of California

Ca2+entry into neurons is facilitated by cooperative gating of clustered Cav1.3 channels

  • Author(s): Moreno, CM
  • Dixon, RE
  • Tajada, S
  • Yuan, C
  • Opitz-Araya, X
  • Binder, MD
  • Santana, LF
  • et al.

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© Moreno et al. 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 Ca2+influx. CaV1.3Schannels are coupled via a C-terminus-to-C-terminus interaction that requires binding of the incoming Ca2+to calmodulin (CaM) and subsequent binding of CaM to the pre-IQ domain of the channels. Physically-coupled channels facilitate Ca2+currents as a consequence of their higher open probabilities, leading to increased firing rates in rat hippocampal neurons. We propose that cooperative gating of CaV1.3Schannels represents a mechanism for the regulation of Ca2+signaling and electrical activity.

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