The Importance of Peptide-Membrane Interactions in Toxin Inhibitions of Sodium Channels

Abstract

Peptide toxins isolated from spiders and cone snails are potent inhibitors of human voltage-gated sodium channels (NaV). Some of these peptides are selective against subtypes NaV1.7 and NaV1.8, reported to be involved in nociception, and may thus have potential as pain therapeutic leads. Peptide toxins can inhibit NaV activity by blocking the pore domain (i.e, pore blockers) or by binding to the membrane-embedded voltage sensor domain of the sodium channel (i.e. gating-modifier toxins). It is still not known how and if gating-modifier toxins also interact with lipid membranes where voltage-sensor domains are located and whether peptide-lipid interactions are relevant for their inhibitory activity at the sodium channel. Using a range of biophysical techniques, we have examined the importance of membrane binding on the inhibitory activity of a subset of peptides, showing for the first time a direct correlation between membrane binding affinity and NaV.7 and NaV1.8 inhibition, highlighting the importance of considering potential membrane-binding events when designing sodium channel voltage-gating modifier inhibitors.