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

Chuanling Yin; Fanpeng Zeng; Puyi Huang; Zhengqi Shi; Qianyi Yang; Zhenduo Pei; Xin Wang; Longhui Chai; Shipei Zhang; Shilong Yang; Wenqi Dong; Xiancui Lu; Yunfei Wang

doi:10.3390/toxins15010070

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

Toxins (Basel). 2023 Jan 12;15(1):70. doi: 10.3390/toxins15010070.

Authors

Affiliation

¹ College of Wildlife and Protected Area, Northeast Forestry University, Harbin 150040, China.

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 (BK_Ca). 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 BK_Ca 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.

Keywords: KCNK18; defensive strategy; paxilline; skin secretion; tree frogs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anura*
Indoles* / pharmacology
Potassium Channels / metabolism
Rats

Substances

Indoles
paxilline
Potassium Channels

Grants and funding

This research was funded by the National Natural Science Foundation of China (32000310 and 32030013), the Natural Science Foundation of Heilongjiang Province (YQ2021H001) and the Fundamental Research Funds for the Central Universities (2572020BE05) to Y.W; the National Natural Science Foundation of China (32022010 and 32170486), the Natural Science Foundation of Heilongjiang Province (JQ2021C001) and the National Forestry and Grassland Administration (2020132610) to S.Y.; and the National Natural Science Foundation of China (32100372) and the Natural Science Foundation of Heilongjiang Province (YQ2022H001) to X.L.