The gating charge pathway of an epilepsy-associated potassium channel accommodates chemical ligands

Ping Li, Zhuxi Chen, Haiyan Xu, Haifeng Sun, Hao Li, Hong Liu, Huaiyu Yang, Zhaobing Gao, Hualiang Jiang, Min Li

Research output: Contribution to journalArticle

Abstract

Voltage-gated potassium (Kv) channels derive their voltage sensitivity from movement of gating charges in voltage-sensor domains (VSDs). The gating charges translocate through a physical pathway in the VSD to open or close the channel. Previous studies showed that the gating charge pathways of Shaker and Kv1.2-2.1 chimeric channels are occluded, forming the structural basis for the focused electric field and gating charge transfer center. Here, we show that the gating charge pathway of the voltage-gated KCNQ2 potassium channel, activity reduction of which causes epilepsy, can accommodate various small molecule ligands. Combining mutagenesis, molecular simulation and electrophysiological recording, a binding model for the probe activator, ztz240, in the gating charge pathway was defined. This information was used to establish a docking-based virtual screening assay targeting the defined ligand-binding pocket. Nine activators with five new chemotypes were identified, and in vivo experiments showed that three ligands binding to the gating charge pathway exhibit significant anti-epilepsy activity. Identification of various novel activators by virtual screening targeting the pocket supports the presence of a ligand-binding site in the gating charge pathway. The capability of the gating charge pathway to accommodate small molecule ligands offers new insights into the gating charge pathway of the therapeutically relevant KCNQ2 channel.

Original languageEnglish (US)
Pages (from-to)1106-1118
Number of pages13
JournalCell Research
Volume23
Issue number9
DOIs
StatePublished - Sep 1 2013

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Keywords

  • KCNQ2 activator
  • anti-epilepsy drug
  • binding site
  • gating charge pathway
  • voltage-gated potassium channel

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Li, P., Chen, Z., Xu, H., Sun, H., Li, H., Liu, H., Yang, H., Gao, Z., Jiang, H., & Li, M. (2013). The gating charge pathway of an epilepsy-associated potassium channel accommodates chemical ligands. Cell Research, 23(9), 1106-1118. https://doi.org/10.1038/cr.2013.82