Alternative splicing controls G protein-dependent inhibition of N-type calcium channels in nociceptors.
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.
Raingo
Jesica
J
Department of Neuroscience, Brown University, Sidney E. Frank Hall for Life Sciences, 185 Meeting Street, Providence, Rhode Island 02912, USA.
Castiglioni
Andrew J
AJ
Lipscombe
Diane
D
D017398:Alternative Splicing; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000502:physiology*; D002460:Cell Line; D004558:Electric Stimulation / Q000379:methods; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005091:Exons / Q000502:physiology; D018755:GABA Agonists / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008969:Molecular Sequence Data; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D009619:Nociceptors / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D014162:Transfection / Q000379:methods
D000701:Analgesics, Opioid; C503279:Cacna1b protein, rat; D020864:Calcium Channels, N-Type; D004791:Enzyme Inhibitors; D018755:GABA Agonists; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D019204:GTP-Binding Proteins; D001418:Baclofen; D002118:Calcium