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Proc Natl Acad Sci U S A. 2017 Nov 7;114(45):E9702-E9711. doi: 10.1073/pnas.1705802114. Epub 2017 Oct 23.

PIP2 mediates functional coupling and pharmacology of neuronal KCNQ channels.

Author information

1
Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada T6G 2R3.
2
Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, DK-2100 Copenhagen, Denmark.
3
Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada T6G 2R3; kurata@ualberta.ca.

Abstract

Retigabine (RTG) is a first-in-class antiepileptic drug that suppresses neuronal excitability through the activation of voltage-gated KCNQ2-5 potassium channels. Retigabine binds to the pore-forming domain, causing a hyperpolarizing shift in the voltage dependence of channel activation. To elucidate how the retigabine binding site is coupled to changes in voltage sensing, we used voltage-clamp fluorometry to track conformational changes of the KCNQ3 voltage-sensing domains (VSDs) in response to voltage, retigabine, and PIP2. Steady-state ionic conductance and voltage sensor fluorescence closely overlap under basal PIP2 conditions. Retigabine stabilizes the conducting conformation of the pore and the activated voltage sensor conformation, leading to dramatic deceleration of current and fluorescence deactivation, but these effects are attenuated upon disruption of channel:PIP2 interactions. These findings reveal an important role for PIP2 in coupling retigabine binding to altered VSD function. We identify a polybasic motif in the proximal C terminus of retigabine-sensitive KCNQ channels that contributes to VSD-pore coupling via PIP2, and thereby influences the unique gating effects of retigabine.

KEYWORDS:

KCNQ channel; electrophysiology; epilepsy; potassium channel; voltage-clamp fluorometry

PMID:
29078287
PMCID:
PMC5692535
DOI:
10.1073/pnas.1705802114
[Indexed for MEDLINE]
Free PMC Article

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