Ligand activation mechanisms of human KCNQ2 channel

Demin Ma, Yueming Zheng, Xiaoxiao Li, Xiaoyu Zhou, Zhenni Yang, Yan Zhang, Long Wang, Wenbo Zhang, Jiajia Fang, Guohua Zhao, Panpan Hou, Fajun Nan, Wei Yang, Nannan Su, Zhaobing Gao () and Jiangtao Guo ()
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Demin Ma: Zhejiang University School of Medicine
Yueming Zheng: Chinese Academy of Sciences
Xiaoxiao Li: Zhejiang University School of Medicine
Xiaoyu Zhou: Chinese Academy of Sciences
Zhenni Yang: Zhejiang University School of Medicine
Yan Zhang: Zhejiang University School of Medicine
Long Wang: Chinese Academy of Sciences
Wenbo Zhang: Chinese Academy of Sciences
Jiajia Fang: Zhejiang University School of Medicine
Guohua Zhao: Zhejiang University School of Medicine
Panpan Hou: Macau University of Science and Technology
Fajun Nan: Chinese Academy of Sciences
Wei Yang: Zhejiang University School of Medicine
Nannan Su: Zhejiang University School of Medicine
Zhaobing Gao: Chinese Academy of Sciences
Jiangtao Guo: Zhejiang University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract The human voltage-gated potassium channel KCNQ2/KCNQ3 carries the neuronal M-current, which helps to stabilize the membrane potential. KCNQ2 can be activated by analgesics and antiepileptic drugs but their activation mechanisms remain unclear. Here we report cryo-electron microscopy (cryo-EM) structures of human KCNQ2-CaM in complex with three activators, namely the antiepileptic drug cannabidiol (CBD), the lipid phosphatidylinositol 4,5-bisphosphate (PIP2), and HN37 (pynegabine), an antiepileptic drug in the clinical trial, in an either closed or open conformation. The activator-bound structures, along with electrophysiology analyses, reveal the binding modes of two CBD, one PIP2, and two HN37 molecules in each KCNQ2 subunit, and elucidate their activation mechanisms on the KCNQ2 channel. These structures may guide the development of antiepileptic drugs and analgesics that target KCNQ2.

Date: 2023
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DOI: 10.1038/s41467-023-42416-x

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