Alternative splicing controls G protein-dependent inhibition of N-type calcium channels in nociceptors

Nat Neurosci. 2007 Mar;10(3):285-92. doi: 10.1038/nn1848. Epub 2007 Feb 11.


Neurotransmitter release from mammalian sensory neurons is controlled by Ca(V)2.2 N-type calcium channels. N-type channels are a major target of neurotransmitters and drugs that inhibit calcium entry, transmitter release and nociception through their specific G protein-coupled receptors. G protein-coupled receptor inhibition of these channels is typically voltage-dependent and mediated by Gbetagamma, whereas N-type channels in sensory neurons are sensitive to a second G protein-coupled receptor pathway that inhibits the channel independent of voltage. Here we show that preferential inclusion in nociceptors of exon 37a in rat Cacna1b (encoding Ca(V)2.2) creates, de novo, a C-terminal module that mediates voltage-independent inhibition. This inhibitory pathway requires tyrosine kinase activation but not Gbetagamma. A tyrosine encoded within exon 37a constitutes a critical part of a molecular switch controlling N-type current density and G protein-mediated voltage-independent inhibition. Our data define the molecular origins of voltage-independent inhibition of N-type channels in the pain pathway.

Publication types

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

MeSH terms

  • Alternative Splicing*
  • Analgesics, Opioid / pharmacology
  • Animals
  • Baclofen / pharmacology
  • Calcium / metabolism
  • Calcium Channels, N-Type / physiology*
  • Cell Line
  • Electric Stimulation / methods
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Exons / physiology
  • GABA Agonists / pharmacology
  • GTP-Binding Proteins / physiology*
  • Guanosine 5'-O-(3-Thiotriphosphate) / pharmacology
  • Humans
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Membrane Potentials / radiation effects
  • Molecular Sequence Data
  • Neural Inhibition / drug effects
  • Neural Inhibition / physiology*
  • Neural Inhibition / radiation effects
  • Nociceptors / physiology*
  • Patch-Clamp Techniques / methods
  • Rats
  • Transfection / methods


  • Analgesics, Opioid
  • Cacna1b protein, rat
  • Calcium Channels, N-Type
  • Enzyme Inhibitors
  • GABA Agonists
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • GTP-Binding Proteins
  • Baclofen
  • Calcium

Associated data

  • GENBANK/AF055477
  • GENBANK/AF286488
  • GENBANK/AY211499
  • GENBANK/M88751