The toxic natural product tutin causes epileptic seizures in mice by activating calcineurin

• Published in: Signal transduction and targeted therapy Vol. 8; no. 1; p. 101
• Main Authors: Han, Qing-Tong, Yang, Wan-Qi, Zang, Caixia, Zhou, Linchao, Zhang, Chong-Jing, Bao, Xiuqi, Cai, Jie, Li, Fangfei, Shi, Qinyan, Wang, Xiao-Liang, Qu, Jing, Zhang, Dan, Yu, Shi-Shan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.03.2023; Nature Publishing Group
• Subjects: 631/378/1689; 631/92/555; Animal models; Animals; Calcineurin; Calcineurin - genetics; Calcineurin - metabolism; Calcium channels (voltage-gated); Cancer Research; Cell Biology; Convulsions & seizures; Drug development; Epilepsy; Epilepsy - chemically induced; Epilepsy - drug therapy; Epilepsy - genetics; Glutamate receptors; Glutamic acid receptors (ionotropic); Internal Medicine; Medicine; Medicine & Public Health; Mice; N-Methyl-D-aspartic acid receptors; Natural products; Oncology; Pathology; Picrotoxin; Proteomes; Receptors, GABA - metabolism; Receptors, N-Methyl-D-Aspartate; Seizures; Seizures - chemically induced; Seizures - genetics; γ-Aminobutyric acid
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-023-01312-y

Tutin, an established toxic natural product that causes epilepsy in rodents, is often used as a tool to develop animal model of acute epileptic seizures. However, the molecular target and toxic mechanism of tutin were unclear. In this study, for the first time, we conducted experiments to clarify the targets in tutin-induced epilepsy using thermal proteome profiling. Our studies showed that calcineurin (CN) was a target of tutin, and that tutin activated CN, leading to seizures. Binding site studies further established that tutin bound within the active site of CN catalytic subunit. CN inhibitor and calcineurin A (CNA) knockdown experiments in vivo proved that tutin induced epilepsy by activating CN, and produced obvious nerve damage. Together, these findings revealed that tutin caused epileptic seizures by activating CN. Moreover, further mechanism studies found that N -methyl- D -aspartate (NMDA) receptors, gamma-aminobutyric acid (GABA) receptors and voltage- and Ca 2+ - activated K + (BK) channels might be involved in related signaling pathways. Our study fully explains the convulsive mechanism of tutin, which provides new ideas for epilepsy treatment and drug development.