Synergetic Action of Domain II and IV Underlies Persistent Current Generation in Na(v)1.3 as revealed by a tarantula toxin

The persistent current (I(NaP)) through voltage-gated sodium channels enhances neuronal excitability by causing prolonged depolarization of membranes. Na(v)1.3 intrinsically generates a small I(NaP), although the mechanism underlying its generation remains unclear. In this study, the involvement of the four domains of Na(v)1.3 in I(NaP) generation was investigated using the tarantula toxin α-hexatoxin-MrVII (RTX-VII). RTX-VII activated Na(v)1.3 and induced a large I(NaP). A pre-activated state binding model was proposed to explain the kinetics of toxin-channel interaction. Of the four domains of Na(v)1.3, both domain II and IV might play important roles in the toxin-induced I(NaP). Domain IV constructed the binding site for RTX-VII, while domain II might not participate in interacting with RTX-VII but could determine the efficacy of RTX-VII. Our results based on the use of RTX-VII as a probe suggest that domain II and IV cooperatively contribute to the generation of I(NaP) in Na(v)1.3.