Dynamic switching of calmodulin interactions underlies Ca2+ regulation of CaV1.3 channels

Nat Commun. 2013;4:1717. doi: 10.1038/ncomms2727.

Abstract

Calmodulin regulation of CaV channels is a prominent Ca(2+) feedback mechanism orchestrating vital adjustments of Ca(2+) entry. The long-held structural correlation of this regulation has been Ca(2+)-bound calmodulin, complexed alone with an IQ domain on the channel carboxy terminus. Here, however, systematic alanine mutagenesis of the entire carboxyl tail of an L-type CaV1.3 channel casts doubt on this paradigm. To identify the actual molecular states underlying channel regulation, we develop a structure-function approach relating the strength of regulation to the affinity of underlying calmodulin/channel interactions, by a Langmuir relation (individually transformed Langmuir analysis). Accordingly, we uncover frank exchange of Ca(2+)-calmodulin to interfaces beyond the IQ domain, initiating substantial rearrangements of the calmodulin/channel complex. The N-lobe of Ca(2+)-calmodulin binds an N-terminal spatial Ca(2+) transforming element module on the channel amino terminus, whereas the C-lobe binds an EF-hand region upstream of the IQ domain. This system of structural plasticity furnishes a next-generation blueprint for CaV channel modulation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Calcium / metabolism*
  • Calcium Channels, L-Type / chemistry
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / metabolism*
  • Calmodulin / metabolism*
  • HEK293 Cells
  • Humans
  • Structure-Activity Relationship

Substances

  • Calcium Channels, L-Type
  • Calmodulin
  • alpha1D (Cav1.3) L-type calcium channel, human
  • Calcium