Isolation and identification of toxins inhibiting Shal potassium channels from the venom of Ornithoctonus hainana spider.

The spider, Ornithoctonus hainana, is a large and formidable predatory arthropod that possesses strong lethality towards rodents through its venoms. Its venom and constituent bioactive peptide toxins have previously been shown to modulate the activity of voltage-gated ion channels. Therefore, venom toxins are an important weapon for rapidly subduing prey or escaping predators. Here, we discovered three new peptide toxins, termed HNTXs, from the venom of O. hainana. These toxins potently inhibit the peak currents of rKv4.2, a member of the Shal channel family. We demonstrated that HNTXs are gating modifiers that shift the voltage dependence of activation and inactivation to more positive potentials. Additionally, chimeric channel and site-directed mutagenesis analyses show that these toxins inhibit rKv4.2 by interacting with the S3-S4 linker in the channel. Furthermore, we found that HNTXs exhibited different responses to Shal channels of vertebrates and invertebrates, suggesting that venomous animals employ diversified toxins to efficiently and accurately defend against predation and interspecific competition. This research may expand our understanding of venom peptides in evolutionary adaptation.