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J. Biol. Chem., Vol. 279, Issue 23, 24826-24833, June 4, 2004

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Novel Isoforms of the Sodium Channels Na_v1.8 and Na_v1.5 Are Produced by a Conserved Mechanism in Mouse and Rat^*

Niall C. H. Kerr, Fiona E. Holmes, and David Wynick¶

From the aboratories for Integrated Neuroscience and Endocrinology (LINE), Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, United Kingdom and NeuroTargets Ltd., Surrey Technology Centre, Occam Road, Surrey Research Park, Guilford, Surrey GU2 7YG, United Kingdom

The voltage-gated sodium channel Na_v1.8 is only expressed in subsets of neurons in dorsal root ganglia (DRG) and trigeminal and nodose ganglia. We have isolated mouse partial length Na_v1.8 cDNA clones spanning the exon 17 sequence, which have 17 nucleotide substitutions and 12 predicted amino acid differences from the published sequence. The absence of a mutually exclusive alternative exon 17 was confirmed by sequencing 4.1 kilobases of genomic DNA spanning exons 16-18 of Scn10a. A novel cDNA isoform was identified, designated Na_v1.8c, which results from alternative 3'-splice site selection at a CAG/CAG motif to exclude the codon for glutamine 1031 within the interdomain cytoplasmic loop IDII/III. The ratio of Na_v1.8c (CAG-skipped) to Na_v1.8 (CAG-inclusive) mRNA in mouse is 2:1 in adult DRG, trigeminal ganglion, and neonatal DRG. A Na_v1.8c isoform also occurs in rat DRG, but is less common. Of the two other tetrodotoxin-resistant channels, no analogous alternative splicing of mouse Na_v1.9 was detected, whereas rare alternative splicing of Na_v1.5 at a CAG/CAG motif resulted in the introduction of a CAG trinucleotide. This isoform, designated Na_v1.5c, is conserved in rat and encodes an additional glutamine residue that disrupts a putative CK2 phosphorylation site. In summary, novel isoforms of Na_v1.8 and Na_v1.5 are each generated by alternative splicing at CAG/CAG motifs, which result in the absence or presence of predicted glutamine residues within the interdomain cytoplasmic loop IDII/III. Mutations of sodium channels within this cytoplasmic loop have previously been demonstrated to alter electrophysiological properties and cause cardiac arrhythmias and epilepsy.

Received for publication, February 5, 2004 , and in revised form, March 17, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AJ623269 (mouse Na_v1.8 cDNA), AJ623270 (mouse Na_v1.8c cDNA), AJ622906 (mouse Scn10a exons 16-18), AJ623271 (rat Na_v1.8c cDNA), AJ623272 (rat Na_v1.5c cDNA), AJ623273 (mouse Na_v1.5c cDNA), and AJ623274 (mouse Na_v1.5 cDNA).

^* This work was supported by the Medical Research Council (MRC) and the Biotechnology and Biological Sciences Research Council (BBSRC). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: LINE, Dorothy Hodgkin Building, Whitson St., Bristol BS1 3NY, UK. Tel.: 44-0-117-3313085; Fax: 44-0-117-3313084; E-mail: d.wynick{at}bristol.ac.uk.

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