Sigma-1 receptor agonists directly inhibit Nav1.2/1.4 channels

PLoS One. 2012;7(11):e49384. doi: 10.1371/journal.pone.0049384. Epub 2012 Nov 5.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dextromethorphan / pharmacology*
  • GTP-Binding Proteins / metabolism
  • Guanidines / pharmacology*
  • HEK293 Cells
  • Humans
  • Ion Channel Gating / drug effects
  • Lidocaine / pharmacology
  • Muscle Proteins / antagonists & inhibitors*
  • Muscle Proteins / metabolism
  • Mutagenesis, Site-Directed
  • Mutant Proteins / metabolism
  • Mutation / genetics
  • NAV1.2 Voltage-Gated Sodium Channel / metabolism*
  • Neurons / drug effects
  • Neurons / metabolism
  • Phenazocine / analogs & derivatives*
  • Phenazocine / pharmacology
  • Protein Kinase C / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Rats
  • Receptors, sigma / agonists*
  • Receptors, sigma / metabolism
  • Sigma-1 Receptor
  • Signal Transduction / drug effects
  • Sodium Channels / metabolism
  • Transfection

Substances

  • Guanidines
  • Muscle Proteins
  • Mutant Proteins
  • NAV1.2 Voltage-Gated Sodium Channel
  • Protein Kinase Inhibitors
  • Receptors, sigma
  • Scn2A protein, rat
  • Scn4a protein, rat
  • Sodium Channels
  • Dextromethorphan
  • SK&F 10047
  • Lidocaine
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C
  • GTP-Binding Proteins
  • Phenazocine
  • 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.