Protoxin-I

Protoxin-I belongs to the inhibitory cystine knot (ICK) family of peptide toxins, which have been known to potently inhibit voltage-gated ion channels.

[5] These loss-of-function replacements primarily represent residues in the hydrophobic patch and positively- and negatively charged rings, further supporting the idea that these regions play an important role in ion channel binding.

[8] Like other gating-modifier spider toxins, Protoxin-I preferentially binds to anionic lipid-containing membranes where it exhibits complex allosteric interactions with ion channel voltage sensor domains.

[11][12] Similar to other gating-modifier toxins of the ICK family, Protoxin-I works by shifting the voltage dependence of activation of voltage-gated sodium channels to more positive potentials.

[8] This notion is further back by the fact that Protoxin-I binds less potently to NaV1.4 and NaV1.5, which exhibit relatively fewer anionic residues on the voltage sensor domain.

[5] In vivo testing in mice revealed that intrathecal injection of Protoxin-I reduces the response to formalin in acute pain and inflammation without signs of neurotoxicity.

[5] This may provide a deeper insight into the biophysiological function and mechanisms underlying TRPA1, with potential clinical applications in pain and inflammation treatment.