Inherent fast inactivation particle of Nav channels as a new binding site for a neurotoxin.

Abstract

Neurotoxins derived from animal venoms are indispensable tools for probing the structure and function of voltage-gated sodium (Nav) channels. Utilizing a novel centipede peptide toxin called rpTx1, we show that the "inherent inactivation particle" of Nav channels represents a binding site for a neurotoxin. The toxin comprises two functional domains: one for cell penetration and one for modulating Nav channel activity. After crossing the cell membrane, rpTx1 preferentially binds to and stabilizes the IFMT motif (the conserved core region of the fast inactivation particle in mammalian Nav channels) in the unbound state, preventing this motif from associating with its receptor site and thereby inhibiting the fast inactivation of Nav channels. This competition between rpTx1 and the receptor site for interacting with the IFMT motif may account for the higher activity of rpTx1 on Nav1.8 than on other Nav subtypes, given the weaker relative affinity between the receptor site and the IFMT motif of Nav1.8. Overall, this study should promote the investigation of the intracellular modulation of Nav channels by neurotoxins.