Differential role of N-type calcium channel splice isoforms in pain.
N-type calcium channels are essential mediators of spinal nociceptive transmission. The core subunit of the N-type channel is encoded by a single gene, and multiple N-type channel isoforms can be generated by alternate splicing. In particular, cell-specific inclusion of an alternatively spliced exon 37a generates a novel form of the N-type channel that is highly enriched in nociceptive neurons and, as we show here, downregulated in a neuropathic pain model. Splice isoform-specific small interfering RNA silencing in vivo reveals that channels containing exon 37a are specifically required for mediating basal thermal nociception and for developing thermal and mechanical hyperalgesia during inflammatory and neuropathic pain. In contrast, both N-type channel isoforms (e37a- and e37b-containing) contribute to tactile neuropathic allodynia. Hence, exon 37a acts as a molecular switch that tailors the channels toward specific roles in pain.
Altier
Christophe
C
Hotchkiss Brain Institute, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada T2N 1N4.
Dale
Camila S
CS
Kisilevsky
Alexandra E
AE
Chapman
Kevin
K
Castiglioni
Andrew J
AJ
Matthews
Elizabeth A
EA
Evans
Rhian M
RM
Dickenson
Anthony H
AH
Lipscombe
Diane
D
Vergnolle
Nathalie
N
Zamponi
Gerald W
GW
D017398:Alternative Splicing; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D020864:Calcium Channels, N-Type / Q000145:classification / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005727:Ganglia, Spinal / Q000166:cytology; D006930:Hyperalgesia / Q000145:classification / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009437:Neuralgia / Q000145:classification / Q000188:drug therapy / Q000235:genetics*; D009475:Neurons, Afferent / Q000187:drug effects; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013373:Substance P / Q000378:metabolism
C503279:Cacna1b protein, rat; D020864:Calcium Channels, N-Type; D034741:RNA, Small Interfering; D013373:Substance P