Abstract
Spider venoms are complex mixtures of biologically active components with potentially interesting applications for drug discovery or for agricultural purposes. The spider Phoneutria nigriventer is responsible for a number of envenomations with sometimes severe clinical manifestations in humans. A more efficient treatment requires a comprehensive knowledge of the venom composition and of the action mechanism of the constituting components. PnTx2-1 (also called δ-ctenitoxin-Pn1a) is a 53-amino-acid-residue peptide isolated from the venom fraction PhTx2. Although PnTx2-1 is classified as a neurotoxin, its molecular target has remained unknown. This study describes the electrophysiological characterization of PnTx2-1 as a modulator of voltage-gated sodium channels. PnTx2-1 is investigated for its activity on seven mammalian Na(V)-channel isoforms, one insect Na(V) channel and one arachnid Na(V) channel. Furthermore, comparison of the activity of both PnTx2-1 and PnTx2-6 on Na(V)1.5 channels reveals that this family of Phoneutria toxins modulates the cardiac Na(V) channel in a bifunctional manner, resulting in an alteration of the inactivation process and a reduction of the sodium peak current.