Article abstract
Nature Neuroscience 10, 285 - 292 (2007)
Published online: 11 February 2007 | doi:10.1038/nn1848
Alternative splicing controls G protein–dependent inhibition of N-type calcium channels in nociceptors
Jesica Raingo1, Andrew J Castiglioni1,2 & Diane Lipscombe1
Abstract
Neurotransmitter release from mammalian sensory neurons is controlled by CaV2.2 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 G
, 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 CaV2.2) creates, de novo, a C-terminal module that mediates voltage-independent inhibition. This inhibitory pathway requires tyrosine kinase activation but not G. 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.
- Department of Neuroscience, Brown University, Sidney E. Frank Hall for Life Sciences, 185 Meeting Street, Providence, Rhode Island 02912, USA.
- Present address: Department of Anesthesiology, Northwestern University, 303 East Chicago Avenue, Chicago, Illinois 60611, USA.
Correspondence to: Diane Lipscombe1 e-mail: Diane_Lipscombe@brown.edu
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