title: Inhibition of voltage-gated Na(+)  currents in sensory neurones by the sea anemone toxin APETx2.
abstract: OBJECTIVE
  APETx2, a toxin from the sea anemone Anthropleura elegantissima, inhibits acid-sensing ion channel 3 (ASIC3)-containing homo- and heterotrimeric channels with IC(50) values < 100 nM and 0.1-2 µM respectively. ASIC3 channels mediate acute acid-induced and inflammatory pain response and APETx2 has been used as a selective pharmacological tool in animal studies. Toxins from sea anemones also modulate voltage-gated Na(+) channel (Na(v) ) function. Here we tested the effects of APETx2 on Na(v) function in sensory neurones.
  
  
  METHODS
  Effects of APETx2 on Na(v) function were studied in rat dorsal root ganglion (DRG) neurones by whole-cell patch clamp.
  
  
  RESULTS
  APETx2 inhibited the tetrodotoxin (TTX)-resistant Na(v) 1.8 currents of DRG neurones (IC(50) , 2.6 µM). TTX-sensitive currents were less inhibited. The inhibition of Na(v) 1.8 currents was due to a rightward shift in the voltage dependence of activation and a reduction of the maximal macroscopic conductance. The inhibition of Na(v) 1.8 currents by APETx2 was confirmed with cloned channels expressed in Xenopus oocytes. In current-clamp experiments in DRG neurones, the number of action potentials induced by injection of a current ramp was reduced by APETx2.
  
  
  CONCLUSIONS
  APETx2 inhibited Na(v) 1.8 channels, in addition to ASIC3 channels, at concentrations used in in vivo studies. The limited specificity of this toxin should be taken into account when using APETx2 as a pharmacological tool. Its dual action will be an advantage for the use of APETx2 or its derivatives as analgesic drugs.
authors.affiliation: Département de Pharmacologie et Toxicologie, Université de Lausanne, Lausanne, Switzerland.
authors.forename: Maxime G
authors.initials: MG
authors.lastname: Blanchard
authors.forename: Lachlan D
authors.initials: LD
authors.lastname: Rash
authors.forename: Stephan
authors.initials: S
authors.lastname: Kellenberger
mesh_terms: D062565:Acid Sensing Ion Channels; D000818:Animals; D003064:Cnidarian Venoms / Q000494:pharmacology*; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D012615:Sea Anemones; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: C501880:APETx2 protein, Anthopleura elegantissima; C568269:ASIC3 protein, rat; D062565:Acid Sensing Ion Channels; D003064:Cnidarian Venoms; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C568319:Scn10a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels