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; Jiangtao Guo

doi:10.1038/s41467-023-42416-x

Ligand activation mechanisms of human KCNQ2 channel

Nat Commun. 2023 Oct 19;14(1):6632. doi: 10.1038/s41467-023-42416-x.

Authors

Demin Ma^#^{1

2}, Yueming Zheng^#^{3

4}, Xiaoxiao Li^#^{1

2}, Xiaoyu Zhou^#^{3

4}, Zhenni Yang^{1

2}, Yan Zhang^{1

2}, Long Wang³, Wenbo Zhang³, Jiajia Fang⁵, Guohua Zhao⁵, Panpan Hou⁶, Fajun Nan^{3

4}, Wei Yang¹, Nannan Su¹, Zhaobing Gao^{7

8

9}, Jiangtao Guo^{10

11

12

13

14

15

16}

Affiliations

¹ Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
² Nanhu Brain-computer Interface Institute, Hangzhou, 311100, China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
⁴ University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing, 100049, China.
⁵ Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China.
⁶ Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR, China.
⁷ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. zbgao@simm.ac.cn.
⁸ University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing, 100049, China. zbgao@simm.ac.cn.
⁹ Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528437, China. zbgao@simm.ac.cn.
¹⁰ Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China. jiangtaoguo@zju.edu.cn.
¹¹ Nanhu Brain-computer Interface Institute, Hangzhou, 311100, China. jiangtaoguo@zju.edu.cn.
¹² Department of Cardiology, Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China. jiangtaoguo@zju.edu.cn.
¹³ Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, Zhejiang, 311121, China. jiangtaoguo@zju.edu.cn.
¹⁴ NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Science and Brain-machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China. jiangtaoguo@zju.edu.cn.
¹⁵ State Key Laboratory of Plant Physiology and Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China. jiangtaoguo@zju.edu.cn.
¹⁶ Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China. jiangtaoguo@zju.edu.cn.

^# Contributed equally.

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.

Publication types

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

MeSH terms

Analgesics*
Anticonvulsants* / pharmacology
Cryoelectron Microscopy
Humans
KCNQ2 Potassium Channel / chemistry
KCNQ2 Potassium Channel / metabolism
KCNQ3 Potassium Channel / metabolism
Ligands
Membrane Potentials

Substances

Anticonvulsants
Ligands
Analgesics
KCNQ2 Potassium Channel
KCNQ3 Potassium Channel
KCNQ2 protein, human