The Bi-Functional Paxilline Enriched in Skin Secretion of Tree Frogs (Hyla japonica) Targets the KCNK18 and BKCa Channels

Abstract

The skin secretion of tree frogs contains a vast array of bioactive chemicals for repelling predators, but their structural and functional diversity is not fully understood. Paxilline (PAX), a compound synthesized by Penicillium paxilli, has been known as a specific antagonist of large conductance Ca2+-activated K+ Channels (BKCa). Here, we report the presence of PAX in the secretions of tree frogs (Hyla japonica) and that this compound has a novel function of inhibiting the potassium channel subfamily K member 18 (KCNK18) channels of their predators. The PAX-induced KCNK18 inhibition is sufficient to evoke Ca2+ influx in charybdotoxin-insensitive DRG neurons of rats. By forming π-π stacking interactions, four phenylalanines located in the central pore of KCNK18 stabilize PAX to block the ion permeation. For PAX-mediated toxicity, our results from animal assays suggest that the inhibition of KCNK18 likely acts synergistically with that of BKCa to elicit tingling and buzzing sensations in predators or competitors. These results not only show the molecular mechanism of PAX-KCNK18 interaction, but also provide insights into the defensive effects of the enriched PAX.

Advanced Research on Animal Venoms in China

“…This research reveals a hitherto unrecognized toxicological role of a vertebrate-derived pore-forming toxin-like protein in the nervous system, which causes hippocampus neuronal cells to undergo pyroptosis, which in turn results in cognitive retardation. Additionally, a study conducted by Chuanling Yin et al [2] has focused on the secretions of tree frogs in order to gain insight into a unique defense mechanism in amphibians. The team has reported the presence of PAX in the secretions of tree frogs (Hyla japonica).…”