Molecular determinant of Na(v)1.8 sodium channel resistance to the venom from the scorpion Leiurus quinquestriatus hebraeus.
The scorpion venom from Leiurus quinquestriatus (LQTX) alters the kinetics of tetrodotoxin (TTX)-sensitive channels such as the skeletal muscle sodium channel Na(v)1.4. In this study, we tested the effects of LQTX on the TTX-resistant sodium current generated by Na(v)1.8 channels in sensory neurons. Na(v)1.8 current was found to be resistant to LQTX, whereas LQTX slowed inactivation of the current generated by Na(v)1.4 and induced a persistent current. LQTX has been shown to bind the S3-S4 linker of domain four (D4S3-S4) of rat brain Na(v)1.2 sodium channels. Sequence analysis shows that the D4S3-S4 linker is longer in Na(v)1.8 than in Na(v)1.4 by four amino acids: Serine; Leucine; Glutamic acid; and Aspargine (SLEN). Na(v)1.4-SLEN, a chimera construct carrying SLEN at the analogous position in the D4S3-S4 linker, was also found to be resistant to LQTX. Therefore, we conclude that the tetrapeptide SLEN at the D4S3-S4 linker region is sufficient to make Na(v)1.8 resistant to LQTX.
D000200:Action Potentials / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D000818:Animals; D002478:Cells, Cultured; D002678:Chimera; D005727:Ganglia, Spinal / Q000187:drug effects / Q000276:immunology; D007113:Immunity, Innate / Q000502:physiology; D015394:Molecular Structure; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009474:Neurons / Q000187:drug effects / Q000276:immunology; D009479:Neuropeptides / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D018408:Patch-Clamp Techniques; D051381:Rats; D012604:Scorpion Venoms / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects* / Q000235:genetics / Q000276:immunology
D062559:NAV1.8 Voltage-Gated Sodium Channel; D009479:Neuropeptides; C568319:Scn10a protein, rat; D012604:Scorpion Venoms; D015222:Sodium Channels