Sigma-1 Receptor Agonists Directly Inhibit NaV1.21.4 Channels 英文参考文献.docVIP

Sigma-1ReceptorAgonistsDirectlyInhibitNaV1.2/1.4 Channels Xiao-FeiGao,Jin-JingYao,Yan-LinHe,ChanglongHu*,Yan-AiMei* School of Life Sciences, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China Abstract (+)-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 Na 1.2 channel currents. The sigma-1 receptor agonists Dextromethorphan (DM) and1,3-di-o-tolyl-guanidine V (DTG) also inhibited NaV1.2 currents through a sigma-1 receptor-independent pathway. The (+)-SKF 10047 inhibition of 1764 1771 in NaV1.2 currents was use- and frequency-dependent. Point mutations demonstrated the importance of Phe the IV-segment 6 domain of the NaV1.2 channel and Phe and Tyr 1579 + 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. Citation: Gao X-F, Yao J-J, He Y-L, Hu C, Mei Y-A (2012) Sigma-1 Receptor Agonists Directly Inhibit NaV1.2/1.4 Channels. PLoS ONE 7(11): e49384. doi:10.1371/ journal.pon