Spider
peptide toxins have attracted attention because of their ability to target voltage-gated
ion channels, which are involved in several pathologies including
chronic pain and some cardiovascular conditions. A class of these
peptides acts by modulating the gating mechanism of voltage-gated
ion channels and are thus called gating modifier toxins (GMTs). In addition to their interactions with voltage-gated
ion channels, some GMTs have affinity for
lipid bilayers. This review discusses the potential importance of the cell membrane on the mode of action of GMTs. We propose that
peptide-membrane interactions can anchor GMTs at the cell surface, thereby increasing GMT concentration in the vicinity of the channel binding site. We also propose that modulating
peptide-membrane interactions might be useful for increasing the therapeutic potential of
spider toxins. Furthermore, we explore the advantages and limitations of the methodologies currently used to examine
peptide-membrane interactions. Although GMT-
lipid membrane binding does not appear to be a requirement for the activity of all GMTs, it is an important feature, and future studies with GMTs should consider the trimolecular
peptide-
lipid membrane-channel complex. This article is part of the Special Issue entitled '
Venom-derived
Peptides as Pharmacological Tools.'