Spider and scorpion knottins targeting voltage-gated sodium ion channels in pain signaling.

In sensory neurons that transmit pain signals, whether acute or chronic, voltage-gated sodium channels (VGSCs) are crucial for regulating excitability. NaV1.1, NaV1.3, NaV1.6, NaV1.7, NaV1.8, and NaV1.9 have been demonstrated and defined their functional roles in pain signaling based on their biophysical properties and distinct patterns of expression in each subtype of sensory neurons. Scorpions and spiders are traditional Chinese medicinal materials, belonging to the arachnid class. Most of the studied species of them have evolved venom peptides that exhibit a wide variety of knottins specifically targeting VGSCs with subtype selectivity and conformational specificity. This review provides an overview on the exquisite knottins from scorpion and spider venoms targeting pain-related NaV channels, describing the sequences and the structural features as well as molecular determinants that influence their selectivity on special subtype and at particular conformation, with an aim for the development of novel research tools on NaV channels and analgesics with minimal adverse effects.