title: Sigma-1 receptor agonists directly inhibit Nav1.2/1.4 channels.
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(V)1.2 and Na(V)1.4 channels independently of sigma-1 receptor activation. (+)-SKF 10047 equally inhibited Na(V)1.2/1.4 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(V)1.2 channel currents. The sigma-1 receptor agonists Dextromethorphan (DM) and 1,3-di-o-tolyl-guanidine (DTG) also inhibited Na(V)1.2 currents through a sigma-1 receptor-independent pathway. The (+)-SKF 10047 inhibition of Na(V)1.2 currents was use- and frequency-dependent. Point mutations demonstrated the importance of Phe(1764) and Tyr(1771) in the IV-segment 6 domain of the Na(V)1.2 channel and Phe(1579) in the Na(V)1.4 channel for (+)-SKF 10047 inhibition. In conclusion, our results suggest that sigma-1 receptor agonists directly inhibit Na(V)1.2/1.4 channels and that these interactions should be given special attention for future sigma-1 receptor function studies.
authors.affiliation: School of Life Sciences, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Gao
authors.forename: Jin-Jing
authors.initials: JJ
authors.lastname: Yao
authors.forename: Yan-Lin
authors.initials: YL
authors.lastname: He
authors.forename: Changlong
authors.initials: C
authors.lastname: Hu
authors.forename: Yan-Ai
authors.initials: YA
authors.lastname: Mei
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003915:Dextromethorphan / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008012:Lidocaine / Q000494:pharmacology; D009124:Muscle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010620:Phenazocine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017480:Receptors, sigma / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015222:Sodium Channels / Q000378:metabolism; D014162:Transfection; D000097605:Sigma-1 Receptor
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases; D003915:Dextromethorphan; D019204:GTP-Binding Proteins; D006146:Guanidines; D008012:Lidocaine; D009124:Muscle Proteins; D050505:Mutant Proteins; D062551:NAV1.2 Voltage-Gated Sodium Channel; D010620:Phenazocine; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D017480:Receptors, sigma; D015222:Sodium Channels; D000097605:Sigma-1 Receptor; C568253:Scn2A protein, rat; C466180:Scn4a protein, rat; C012134:SK&F 10047; C050232:1,3-ditolylguanidine