Cell-specific alternative splicing increases calcium channel current density in the pain pathway.
N-type calcium channels are critical for pain transduction. Inhibitors of these channels are powerful analgesics, but clinical use of current N-type blockers remains limited by undesirable actions in other regions of the nervous system. We now demonstrate that a unique splice isoform of the N-type channel is restricted exclusively to dorsal root ganglia. By a combination of functional and molecular analyses at the single-cell level, we show that the DRG-specific exon, e37a, is preferentially present in Ca(V)2.2 mRNAs expressed in neurons that contain nociceptive markers, VR1 and Na(V)1.8. Cell-specific inclusion of exon 37a correlates closely with significantly larger N-type currents in nociceptive neurons. This unique splice isoform of the N-type channel could represent a novel target for pain management.
Bell
Thomas J
TJ
Department of Neuroscience, Brown University, Providence, RI 02912, USA.
Thaler
Christopher
C
Castiglioni
Andrew J
AJ
Helton
Thomas D
TD
Lipscombe
Diane
D
D017398:Alternative Splicing; D000818:Animals; D020746:Calcium Channels, L-Type / Q000235:genetics* / Q000378:metabolism*; D020864:Calcium Channels, N-Type / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D004553:Electric Conductivity; D005091:Exons; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000235:genetics / Q000503:physiopathology*; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
C503279:Cacna1b protein, rat; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D020033:Protein Isoforms; D002211:Capsaicin