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The Journal of Neuroscience, June 13, 2007, 27(24):6363-6373; doi:10.1523/JNEUROSCI.0307-07.2007

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Neurobiology of Disease
Differential Role of N-Type Calcium Channel Splice Isoforms in Pain

Christophe Altier,1 Camila S. Dale,2 Alexandra E. Kisilevsky,1 Kevin Chapman,2 Andrew J. Castiglioni,3 Elizabeth A. Matthews,4 Rhian M. Evans,1 Anthony H. Dickenson,4 Diane Lipscombe,3 Nathalie Vergnolle,2 and Gerald W. Zamponi1,2

1Hotchkiss Brain Institute, Department of Physiology and Biophysics and 2Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada T2N 1N4, 3Department of Neuroscience, Brown University, Providence, Rhode Island 02912, and 4Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom

Correspondence should be addressed to Dr. Gerald W. Zamponi, Department of Physiology and Biophysics, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1. Email: zamponi{at}ucalgary.ca

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.

Key words: pain; calcium channels; N-type; splice isoforms; siRNA; dorsal root ganglion

Received Sept. 11, 2006; revised April 26, 2007; accepted April 28, 2007.

Correspondence should be addressed to Dr. Gerald W. Zamponi, Department of Physiology and Biophysics, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1. Email: zamponi{at}ucalgary.ca






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