Molecular moieties masking Ca2+-dependent facilitation of voltage-gated Cav2.2 Ca2+ channels

J Gen Physiol. 2018 Jan 2;150(1):83-94. doi: 10.1085/jgp.201711841. Epub 2017 Dec 5.


Voltage-gated Cav2.1 (P/Q-type) Ca2+ channels undergo Ca2+-dependent inactivation (CDI) and facilitation (CDF), both of which contribute to short-term synaptic plasticity. Both CDI and CDF are mediated by calmodulin (CaM) binding to sites in the C-terminal domain of the Cav2.1 α1 subunit, most notably to a consensus CaM-binding IQ-like (IQ) domain. Closely related Cav2.2 (N-type) channels display CDI but not CDF, despite overall conservation of the IQ and additional sites (pre-IQ, EF-hand-like [EF] domain, and CaM-binding domain) that regulate CDF of Cav2.1. Here we investigate the molecular determinants that prevent Cav2.2 channels from undergoing CDF. Although alternative splicing of C-terminal exons regulates CDF of Cav2.1, the splicing of analogous exons in Cav2.2 does not reveal CDF. Transfer of sequences encoding the Cav2.1 EF, pre-IQ, and IQ together (EF-pre-IQ-IQ), but not individually, are sufficient to support CDF in chimeric Cav2.2 channels; Cav2.1 chimeras containing the corresponding domains of Cav2.2, either alone or together, fail to undergo CDF. In contrast to the weak binding of CaM to just the pre-IQ and IQ of Cav2.2, CaM binds to the EF-pre-IQ-IQ of Cav2.2 as well as to the corresponding domains of Cav2.1. Therefore, the lack of CDF in Cav2.2 likely arises from an inability of its EF-pre-IQ-IQ to transduce the effects of CaM rather than weak binding to CaM per se. Our results reveal a functional divergence in the CDF regulatory domains of Cav2 channels, which may help to diversify the modes by which Cav2.1 and Cav2.2 can modify synaptic transmission.

Publication types

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

MeSH terms

  • Alternative Splicing
  • Animals
  • Binding Sites
  • Calcium / metabolism
  • Calcium Channels, N-Type / chemistry
  • Calcium Channels, N-Type / genetics
  • Calcium Channels, N-Type / metabolism*
  • Calmodulin / metabolism*
  • HEK293 Cells
  • Humans
  • Membrane Potentials
  • Protein Binding
  • Rats


  • Cacna1b protein, rat
  • Calcium Channels, N-Type
  • Calmodulin
  • Calcium

Associated data

  • RefSeq/NM_023035
  • RefSeq/NM_001127222
  • RefSeq/NM_000718
  • RefSeq/NM_001127221
  • RefSeq/NM_147141
  • RefSeq/NM_053851
  • RefSeq/NM_000722
  • GENBANK/CM000671
  • GENBANK/AF055477