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The Journal of Neuroscience, July 1, 2002, 22(13):5300-5309
Alternative Splicing of an Insect Sodium Channel Gene Generates Pharmacologically Distinct Sodium Channels
Jianguo Tan1, *, Zhiqi Liu1, *, Yoshiko Nomura1, Alan L. Goldin2, and Ke Dong1 1 Department of Entomology and Neuroscience Program, Michigan State University, East Lansing, Michigan 48824, and 2 Department of Microbiology and Molecular Genetics, University of California, Irvine, California 92697
Alternative splicing is a major mechanism by which potassium and calcium channels increase functional diversity in animals. Extensive alternative splicing of the para sodium channel gene and developmental regulation of alternative splicing have been reported in Drosophila species. Alternative splicing has also been observed for several mammalian voltage-gated sodium channel genes. However, the functional significance of alternative splicing of sodium channels has not been demonstrated. In this study, we identified three mutually exclusive alternative exons encoding part of segments 3 and 4 of domain III in the German cockroach sodium channel gene, paraCSMA. The splice site is conserved in the mouse, fish, and human Nav1.6 sodium channel genes, suggesting an ancient origin. One of the alternative exons possesses a stop codon, which would generate a truncated protein with only the first two domains. The splicing variant containing the stop codon is detected only in the PNS, whereas the other two full-size variants were detected in both the PNS and CNS. When expressed in Xenopus oocytes, the two splicing variants produced robust sodium currents, but with different gating properties, whereas the splicing variant with the stop codon did not produce any detectable sodium current. Furthermore, these two functional splicing variants exhibited a striking difference in sensitivity to a pyrethroid insecticide, deltamethrin. Exon swapping partially reversed the channel sensitivity to deltamethrin. Our results therefore provide the first evidence that alternative splicing of a sodium channel gene produces pharmacologically distinct channels.
Key words: alternative splicing; para; paraCSMA; sodium channel; pyrethroid insecticide; Xenopus oocyte expression system
* J.T. and Z.L. contributed equally to this project.
Copyright © 2002 Society for Neuroscience 0270-6474/02/22135300-10$05.00/0
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