Ligand activation mechanisms of human KCNQ2 channel

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) struct...

Full description

Saved in:
Bibliographic Details
Published in:Nature communications 2023-10, Vol.14 (1), p.6632-6632, Article 6632
Main Authors: Ma, Demin, Zheng, Yueming, Li, Xiaoxiao, Zhou, Xiaoyu, Yang, Zhenni, Zhang, Yan, Wang, Long, Zhang, Wenbo, Fang, Jiajia, Zhao, Guohua, Hou, Panpan, Nan, Fajun, Yang, Wei, Su, Nannan, Gao, Zhaobing, Guo, Jiangtao
Format: Article
Language:English
Subjects:
101/28
631/114
631/45/269/1151
631/57/2270/1140
9/74
Analgesics
Antiepileptic agents
Cannabidiol
Cannabinoids
Channel gating
Conformation
Drug development
Electron microscopy
Electrophysiology
Humanities and Social Sciences
KCNQ2 protein
KCNQ3 protein
Lipids
Membrane potential
multidisciplinary
Phosphatidylinositol 4,5-diphosphate
Potassium
Potassium channels (voltage-gated)
Science
Science (multidisciplinary)
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 (PIP 2 ), 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 PIP 2 , 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. The potassium channel KCNQ2 can be activated by analgesics and antiepileptic drugs via an unclear mechanism. Here authors report structures of KCNQ2-CaM in complex with cannabidiol, PIP2, and HN37 and elucidate the mechanisms of activation.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-42416-x