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This Article Full Text Full Text (PDF) All Versions of this Article: 99/5/2241    most recent 01350.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Chatelier, A. Articles by Chahine, M. Search for Related Content PubMed PubMed Citation Articles by Chatelier, A. Articles by Chahine, M.

Biophysical Properties of Human Na_v1.7 Splice Variants and Their Regulation by Protein Kinase A

¹Centre de Recherche, Université Laval Robert-Giffard, and Department of Medicine, Université Laval, Quebec City, Quebec, Canada; and ²Molecular Pharmacology Department, AstraZeneca R&D Södertälje, Södertälje, Sweden

Submitted 14 December 2007; accepted in final form 4 March 2008

The sodium channel Na_v1.7 is preferentially expressed in nociceptive neurons and is believed to play a crucial role in pain sensation. Four alternative splice variants are expressed in human dorsal root ganglion neurons, two of which differ in exon 5 by two amino acids in the S3 segment of domain I (exons 5A and 5N). Two others differ in exon 11 by the presence (11L) or absence (11S) of an 11 amino acid sequence in the loop between domains I and II, an important region for PKA regulation. In the present study, we used the whole cell configuration of the patch-clamp technique to investigate the biophysical properties and 8-bromo-cyclic adenosine monophosphate (8Br-cAMP) modulation of these splice variants expressed in tsA201 cells in the presence of the β₁-subunit. The alternative splicing of Na_v1.7 had no effect on most of the biophysical properties of this channel, including activation, inactivation, and recovery from inactivation. However, development of inactivation experiments revealed that the isoform containing exon 5A had slower kinetics of inactivation for negative potentials than that of the variant containing exon 5N. This difference was associated with higher ramp current amplitudes for isoforms containing exon 5A. Moreover, 8Br-cAMP–mediated phosphorylation induced a negative shift of the activation curve of variants containing exon 11S, whereas inactivation properties were unchanged. Isoforms with exon 11L were not modulated by 8Br-cAMP–induced phosphorylation. We conclude that alternative splicing of human Na_v1.7 can specifically modulate the biophysical properties and cAMP-mediated regulation of this channel. Changing the proportions of these variants may thus influence neuronal excitability and pain sensation.

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