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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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COS Cells
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Chlorocebus aethiops
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Dextromethorphan / pharmacology*
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GTP-Binding Proteins / metabolism
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Guanidines / pharmacology*
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HEK293 Cells
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Humans
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Ion Channel Gating / drug effects
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Lidocaine / pharmacology
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Muscle Proteins / antagonists & inhibitors*
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Muscle Proteins / metabolism
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Mutagenesis, Site-Directed
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Mutant Proteins / metabolism
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Mutation / genetics
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NAV1.2 Voltage-Gated Sodium Channel / metabolism*
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Neurons / drug effects
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Neurons / metabolism
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Phenazocine / analogs & derivatives*
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Phenazocine / pharmacology
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Protein Kinase C / metabolism
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Protein Kinase Inhibitors / pharmacology
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Rats
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Receptors, sigma / agonists*
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Receptors, sigma / metabolism
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Sigma-1 Receptor
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Signal Transduction / drug effects
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Sodium Channels / metabolism
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Transfection
Substances
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Guanidines
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Muscle Proteins
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Mutant Proteins
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NAV1.2 Voltage-Gated Sodium Channel
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Protein Kinase Inhibitors
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Receptors, sigma
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Scn2A protein, rat
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Scn4a protein, rat
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Sodium Channels
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Dextromethorphan
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SK&F 10047
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Lidocaine
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Cyclic AMP-Dependent Protein Kinases
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Protein Kinase C
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GTP-Binding Proteins
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Phenazocine
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1,3-ditolylguanidine
Grants and funding
This work was supported by a grant from the National Basic Research Program of China (2011CB503703) and the Shanghai Leading Academic Discipline Project [B111]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.