The Sensorless pore module of voltage-gated k-channel family 7 embodies the target site for the anticonvulsant retigabine

Ruhma Syeda, Jose S. Santos, Mauricio Montal

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

KCNQ (voltage-gated K+ channel family 7 (Kv7)) channels control cellular excitability and underlie the K+ current sensitive to muscarinic receptor signaling (theMcurrent) in sympathetic neurons. Here we show that the novel anti-epileptic drug retigabine (RTG) modulates channel function of pore-only modules (PMs) of the human Kv7.2 and Kv7.3 homomeric channels and of Kv7.2/3 heteromeric channels by prolonging the residence time in the open state. In addition, the Kv7 channel PMs are shown to recapitulate the single-channel permeation and pharmacological specificity characteristics of the corresponding full-length proteins in their native cellular context. A mutation (W265L) in the reconstituted Kv7.3 PM renders the channel insensitive to RTG and favors the conductive conformation of the PM, in agreement to what is observed when the Kv7.3 mutant is heterologously expressed. On the basis of the new findings and homology models of the closed and open conformations of the Kv7.3 PM, we propose a structural mechanism for the gating of the Kv7.3PMand for the site of action ofRTGas a Kv7.2/Kv7.3 K+ current activator. The results validate the modular design of human Kv channels and highlight thePMas a high-fidelity target for drug screening of Kv channels.

Original languageEnglish (US)
Pages (from-to)2931-2937
Number of pages7
JournalJournal of Biological Chemistry
Volume291
Issue number6
DOIs
StatePublished - Feb 5 2016

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'The Sensorless pore module of voltage-gated k-channel family 7 embodies the target site for the anticonvulsant retigabine'. Together they form a unique fingerprint.

  • Cite this