XE991 and linopirdine are state-dependent inhibitors for Kv7/KCNQ channels that favor activated single subunits

Derek L. Greene, Seungwoo Kang, Naoto Hoshi

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

M-channel inhibitors, especially XE991, are being used increasingly in animal experiments; however, insufficient characterization of XE991 at times confounds the interpretation of results when using this compound. Here, we demonstrate that XE991 and linopirdine are state-dependent inhibitors that favor the activated-subunit of neuronal Kv7/KCNQ channels. We performed patch-clamp experiments on homomeric Kv7.2 or heteromeric Kv7.2/3 channels expressed in Chinese hamster ovary cells to characterize XE991 and linopirdine. Neither inhibitor was efficacious around the resting membrane potential of cells in physiologic conditions. Inhibition of Kv7.2 and Kv7.2/3 channels by XE991 was closely related with channel activation. When the voltage dependence of activation was left-shifted by retigabine or right-shifted by the mutation, Kv7.2(R214D), the shift in half-activation voltage proportionally coincided with the shift in the half-effective potential for XE991 inhibition. Inhibition kinetics during XE991 wash-in was facilitated at depolarized potentials. Ten-minute washout of XE991 resulted in ∼30% current recovery, most of which was attributed to surface transport of Kv7.2 channels. Linopirdine also exhibited similar inhibition characteristics, with the exception of near-complete current recovery after washout at depolarized potentials. Inhibition kinetics of both XE991 and linopirdine was not as sensitive to changes in voltage as would be predicted by open-channel inhibition. Instead, they were well explained by binding to a single activated subunit. The characteristics of XE991 and linopirdine should be taken into account when these M-channel inhibitors are used in experiments.

Original languageEnglish (US)
Pages (from-to)177-185
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume362
Issue number1
DOIs
StatePublished - Jul 2017
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Fingerprint

Dive into the research topics of 'XE991 and linopirdine are state-dependent inhibitors for Kv7/KCNQ channels that favor activated single subunits'. Together they form a unique fingerprint.

Cite this