μ-conotoxin TsIIIA, a peptide inhibitor of human voltage-gated sodium channel hNa1.8.

TsIIIA, the first μ-conotoxin from Conus tessulatus, can selectively inhibit rat tetrodotoxin-resistant sodium channels. TsIIIA also shows potent analgesic activity in a mice hotplate analgesic assay, but its effect on human sodium channels remains unknown. In this study, eight human sodium channel subtypes, hNa1.1- hNa1.8, were expressed in HEK293 or ND7/23 cells and tested on the chemically synthesized TsIIIA. Patch clamp experiments showed that 10 μM TsIIIA had no effects on the tetrodotoxin-sensitive hNa1.1, hNa1.2, hNa1.3, hNa1.4, hNa1.6 and hNa1.7, as well as tetrodotoxin-resistant hNa1.5. For tetrodotoxin-resistant hNa1.8, concentrations of 1, 5 and 10 μM TsIIIA reduced the hNa1.8 currents to 59.26%, 36.21% and 24.93% respectively. Further detailed dose-effect experiments showed that TsIIIA inhibited hNa1.8 currents with an IC value of 2.11 μM. In addition, 2 μM TsIIIA did not induce a shift in the current-voltage relationship of hNa1.8. Taken together, the hNa1.8 peptide inhibitor TsIIIA provides a pharmacological probe for sodium channels and a potential therapeutic agent for pain.