Inhibition of voltage-gated Na plus currents in sensory neurones by the sea anemone toxin APETx2

BACKGROUND AND PURPOSE APETx2, a toxin from the sea anemone Anthropleura elegantissima, inhibits acid-sensing ion channel 3 (ASIC3)-containing homo- and heterotrimeric channels with IC50 values < 100 nM and 0.12 mu M 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 (Nav) function. Here we tested the effects of APETx2 on Nav function in sensory neurones. EXPERIMENTAL APPROACH Effects of APETx2 on Nav function were studied in rat dorsal root ganglion (DRG) neurones by whole-cell patch clamp. KEY RESULTS APETx2 inhibited the tetrodotoxin (TTX)-resistant Nav 1.8 currents of DRG neurones (IC50, 2.6 mu M). TTX-sensitive currents were less inhibited. The inhibition of Nav 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 Nav 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 AND IMPLICATIONS APETx2 inhibited Nav 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.