8.B.44. The Centipede Spooky Toxin (Scoloptoxin-15) Family
The centipede Spooky toxin (Ssm or SsTx) is of 76 aas with a single N-terminal TMS. It inhibits KCNQ K+ channels (see for example TC subfamily 1.A.1.15). It blocks voltage-gated potassium channels (e.g., Kv7.4/KCNQ4 (IC50=2.5 uM), Kv7.1/KCNQ1 (IC50=2.8 uM), Kv7.2/KCNQ2 (IC50=2.7 uM) and Kv7.5/KCNQ5 (IC50=2.7 uM). It targets the pore domain; in particular negatively charged residues 'Asp-266' and 'Asp-288', of KCNQ4 and probably other KCNQ channel family members where these residues are conserved. In vivo, shows vasoconstrictive activity resulting in acute hypertension when injected intravenously in mice. It also induces coronary vasospasms ultimately leading to heart failure, and induces seizures when injected into the hippocampus of mice. It causes decreased respiratory rates while increasing respiratory amplitude, probably by triggering a contraction of the bronchial ring (Luo et al. 2018).
Venomous animals utilize venom glands to store andsecrete powerful toxins for intraspecific and/or interspecific antagonistic interactions, implying that tissue-specific resistance is essential for venom glands to anatomically separate toxins from other tissues. Wang et al. 2022 revealed the mechanism of tissue-specific resistance in centipedes (Scolopendra subspinipes mutilans), where the splice variant of the receptor repels its own toxin. Unlike the well-known resistance mechanism by mutation in a given exon, they found that the KCNQ1 channel is highly expressed in the venom gland as a unique splice variant in which the pore domain and TMS6, partially encoded by exon 6 (rather than 7 as found in other tissues), contain eleven mutated residues. Such a splice variant is sufficient to gain resistance to SsTx (a lethal toxin for giant prey capture) in the venom gland due to a partially buried binding site. Therefore, the tissue-specific KCNQ1 modification confers resistance to the toxins, establishing a safe zone in the venom-storing/secreting environment (Wang et al. 2022).