Sigma-1 Receptor Agonists Directly Inhibit NaV1.2/1.4 Channels

Xiao Fei Gao, Jin Jing Yao, Yan Lin He, Changlong Hu, Yan Ai Mei

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


(+)-SKF 10047 (N-allyl-normetazocine) is a prototypic and specific sigma-1 receptor agonist that has been used extensively to study the function of sigma-1 receptors. (+)-SKF 10047 inhibits K+, Na+ and Ca2+ channels via sigma-1 receptor activation. We found that (+)-SKF 10047 inhibited NaV1.2 and NaV1.4 channels independently of sigma-1 receptor activation. (+)-SKF 10047 equally inhibited NaV1.2/1.4 channel currents in HEK293T cells with abundant sigma-1 receptor expression and in COS-7 cells, which barely express sigma-1 receptors. The sigma-1 receptor antagonists BD 1063,BD 1047 and NE-100 did not block the inhibitory effects of (+)-SKF-10047. Blocking of the PKA, PKC and G-protein pathways did not affect (+)-SKF 10047 inhibition of NaV1.2 channel currents. The sigma-1 receptor agonists Dextromethorphan (DM) and1,3-di-o-tolyl-guanidine (DTG) also inhibited NaV1.2 currents through a sigma-1 receptor-independent pathway. The (+)-SKF 10047 inhibition of NaV1.2 currents was use- and frequency-dependent. Point mutations demonstrated the importance of Phe1764 and Tyr1771 in the IV-segment 6 domain of the NaV1.2 channel and Phe1579 in the NaV1.4 channel for (+)-SKF 10047 inhibition. In conclusion, our results suggest that sigma-1 receptor agonists directly inhibit NaV1.2/1.4 channels and that these interactions should be given special attention for future sigma-1 receptor function studies.

Original languageEnglish (US)
Article numbere49384
JournalPloS one
Issue number11
StatePublished - Nov 5 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General


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