Molecular interaction of δ-conotoxins with voltage-gated sodium channels

Various neurotoxic peptides modulate voltage-gated sodium (Na-V) channels and thereby affect cellular excitability. delta-Conotoxins from predatory cone snails slow down inactivation of Na-V channels, but their interaction site and mechanism of channel modulation are unknown. Here, we show that delta-conotoxin SVIE from Conus striatus interacts with a conserved hydrophobic triad (YFV) in the domain-4 voltage sensor of Na-V channels. This site overlaps with that of the scorpion a-toxin Lqh-2, but not with the alpha-like toxin Lqh-3 site. delta-SVIE functionally competes with Lqh-2, but exhibits strong cooperativity with Lqh-3, presumably by synergistically trapping the voltage sensor in its on position. (c) 2005 Federation of European Biochemical Societies. All rights reserved.