sigma-1 receptor agonists directly inhibit nav1.21.4 channelssigma 1受体受体激动剂直接抑制nav1.21.4频道.pdfVIP

Sigma-1 Receptor Agonists Directly Inhibit NaV 1.2/1.4 Channels Xiao-Fei Gao, Jin-Jing Yao, Yan-Lin He, Changlong Hu*, Yan-Ai Mei* 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 Na 1.2 and Na 1.4 channels independently of sigma-1 receptor activation. (+)-SKF V V 10047 equally inhibited Na 1.2/1.4 channel currents in HEK293T cells with abundant sigma-1 receptor expression and in V 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 NaV 1.2 channel currents. The sigma-1 receptor agonists Dextromethorphan (DM) and1,3-di-o-tolyl-guanidine (DTG) also inhibited NaV 1.2 currents through a sigma-1 receptor-independent pathway. The (+)-SKF 10047 inhibition of NaV 1.2 currents was use- and frequency-dependent. Point mutations demonstrated the importance of Phe1764 and Tyr1771 in the IV-segment 6 domain of the Na 1.2 channel and Phe1579 in the Na 1.4 channel for (+)-SKF 10047 inhibition. In V V conclusion, our results suggest that sigma-1 receptor agonists directly inhibit NaV 1.2/1.4 channels and that these interactions should be g