Voltage-gated calcium channels function as Ca2+-activated signaling receptors

Trends Biochem Sci. 2014 Feb;39(2):45-52. doi: 10.1016/j.tibs.2013.12.005. Epub 2014 Jan 2.


Voltage-gated calcium channels (VGCCs) are transmembrane cell surface proteins responsible for multifunctional signals. In response to voltage, VGCCs trigger synaptic transmission, drive muscle contraction, and regulate gene expression. Voltage perturbations open VGCCs enabling Ca(2+) binding to the low affinity Ca(2+) binding site of the channel pore. Subsequent to permeation, Ca(2+) targets selective proteins to activate diverse signaling pathways. It is becoming apparent that the Ca(2+)-bound channel triggers secretion in excitable cells and drives contraction in cardiomyocytes prior to Ca(2+) permeation. Here, I highlight recent data implicating receptor-like function of the Ca(2+)-bound channel in converting external Ca(2+) into an intracellular signal. The two sequential mechanistic perspectives of VGCC function are discussed in the context of the prevailing and long-standing current models of depolarization-evoked secretion and cardiac contraction.

Keywords: RyR2; SNAREs; cardiac channel; cardiac contraction; ryanodine receptor; synaptotagmin; syntaxin; transmitter release.

MeSH terms

  • Action Potentials / physiology
  • Animals
  • Calcium / metabolism*
  • Calcium Channels, L-Type / chemistry
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / metabolism*
  • Calcium Signaling / physiology*
  • Excitation Contraction Coupling / physiology
  • Exocytosis
  • Gene Expression
  • Humans
  • Ion Channel Gating / physiology
  • Myocardial Contraction / physiology
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism*
  • Protein Binding
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Ryanodine Receptor Calcium Release Channel / genetics
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • Synaptic Transmission / physiology
  • Synaptotagmin I / genetics
  • Synaptotagmin I / metabolism
  • Syntaxin 1 / genetics
  • Syntaxin 1 / metabolism


  • Calcium Channels, L-Type
  • Receptors, Cell Surface
  • Ryanodine Receptor Calcium Release Channel
  • SYT1 protein, human
  • Synaptotagmin I
  • Syntaxin 1
  • Calcium