Spider Knottin Pharmacology at Voltage-Gated Sodium Channels and Their Potential to Modulate Pain Pathways.

Voltage-gated sodium channels (Na _V s) are a key determinant of neuronal signalling. Neurotoxins from diverse taxa that selectively activate or inhibit Na _V channels have helped unravel the role of Na _V channels in diseases, including chronic pain. Spider venoms contain the most diverse array of inhibitor cystine knot (ICK) toxins (knottins). This review provides an overview on how spider knottins modulate Na _V channels and describes the structural features and molecular determinants that influence their affinity and subtype selectivity. Genetic and functional evidence support a major involvement of Na _V subtypes in various chronic pain conditions. The exquisite inhibitory properties of spider knottins over key Na _V subtypes make them the best lead molecules for the development of novel analgesics to treat chronic pain.