Navβ subunits modulate the inhibition of Nav1.8 by the analgesic gating modifier μO-conotoxin MrVIB

J Pharmacol Exp Ther. 2011 Aug;338(2):687-93. doi: 10.1124/jpet.110.178343. Epub 2011 May 17.


Voltage-gated sodium channels (VGSCs) consist of a pore-forming α-subunit and regulatory β-subunits. Several families of neuroactive peptides of Conus snails target VGSCs, including μO-conotoxins and μ-conotoxins. Unlike μ-conotoxins and the guanidinium alkaloid saxitoxin (STX), which are pore blockers, μO-conotoxins MrVIA and MrVIB inhibit VGSCs by modifying channel gating. μO-MrVIA/B can block Na(v)1.8 (a tetrodotoxin-resistant isoform of VGSCs) and have analgesic properties. The effect of Na(v)β-subunit coexpression on susceptibility to block by μO-MrVIA/B and STX has, until now, not been reported. Here, we show that β1-, β2-, β3-, and β4-subunits, when individually coexpressed with Na(v)1.8 in Xenopus laevis oocytes, increased the k(on) of the block produced by μO-MrVIB (by 3-, 32-, 2-, and 7-fold, respectively) and modestly decreased the apparent k(off). Strong depolarizing prepulses markedly accelerated MrVIB washout with rates dependent on β-subunit coexpression. Thus, coexpression of β-subunits with Na(v)1.8 can strongly influence the affinity of the conopeptide for the channel. This observation is of particular interest because β-subunit expression can be dynamic, e.g., β2-expression is up-regulated after nerve injury (J Neurosci, 25:10970-10980, 2005); therefore, the effectiveness of a μO-conotoxin as a channel blocker could be enhanced by the conditions that may call for its use therapeutically. In contrast to MrVIB's action, the STX-induced block of Na(v)1.8 was only marginally, if at all, affected by coexpression of any of the β-subunits. Our results raise the possibility that μO-conotoxins and perhaps other gating modifiers may provide a means to functionally assess the β-subunit composition of VGSC complexes in neurons.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Analgesics, Non-Narcotic / pharmacology*
  • Animals
  • Conotoxins / pharmacology*
  • Dose-Response Relationship, Drug
  • Female
  • NAV1.8 Voltage-Gated Sodium Channel
  • Oocytes / metabolism
  • Peptide Biosynthesis / drug effects
  • Protein Binding
  • Protein Subunits / antagonists & inhibitors*
  • Protein Subunits / biosynthesis
  • Protein Subunits / physiology*
  • Rats
  • Sodium Channel Blockers / pharmacology*
  • Sodium Channels / metabolism*
  • Sodium Channels / physiology
  • Xenopus laevis


  • Analgesics, Non-Narcotic
  • Conotoxins
  • NAV1.8 Voltage-Gated Sodium Channel
  • Protein Subunits
  • Scn10a protein, rat
  • Sodium Channel Blockers
  • Sodium Channels
  • muO-conotoxin MrVIB