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J. Biol. Chem., Vol. 279, Issue 44, 46234-46241, October 29, 2004

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Expression of Alternatively Spliced Sodium Channel -Subunit Genes

UNIQUE SPLICING PATTERNS ARE OBSERVED IN DORSAL ROOT GANGLIA^*

Christopher K. Raymond, John Castle, Philip Garrett-Engele, Christopher D. Armour, Zhengyan Kan, Nicholas Tsinoremas, and Jason M. Johnson

From the Rosetta Inpharmatics LLC, Seattle, Washington 98109

Molecular medicine requires the precise definition of drug targets, and tools are now in place to provide genome-wide information on the expression and alternative splicing patterns of any known gene. DNA microarrays were used to monitor transcript levels of the nine well-characterized -subunit sodium channel genes across a broad range of tissues from cynomolgus monkey, a non-human primate model. Alternative splicing of human transcripts for a subset of the genes that are expressed in dorsal root ganglia, SCN8A (Na_v1.6), SCN9A (Na_v1.7), and SCN11A (Na_v1.9) was characterized in detail. Genomic sequence analysis among gene family paralogs and between cross-species orthologs suggested specific alternative splicing events within transcripts of these genes, all of which were experimentally confirmed in human tissues. Quantitative PCR revealed that certain alternative splice events are uniquely expressed in dorsal root ganglia. In addition to characterization of human transcripts, alternatively spliced sodium channel transcripts were monitored in a rat model for neuropathic pain. Consistent down-regulation of all transcripts was observed, as well as significant changes in the splicing patterns of SCN8A and SCN9A.

Received for publication, June 8, 2004 , and in revised form, August 3, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY682082, AY682081, AY682083, AY682085, AY682084, AY682086, and AY686224.

^* 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: Rosetta Inpharmatics LLC, a wholly owned subsidiary of Merck & Co., Inc., 401 Terry Ave. North, Seattle, WA 98109. Tel.: 206-802-7358; Fax: 206-802-6411; E-mail: christopher_raymond{at}merck.com.

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