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Nat Commun. 2015 Sep 3;6:8116. doi: 10.1038/ncomms9116.

Atomic basis for therapeutic activation of neuronal potassium channels.

Author information

1
Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3.
2
Department of Molecular Physiology and Biophysics, University of Iowa, 285 Newton Road, Iowa City, Iowa 52242, USA.
3
Department of Cardiovascular Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1 (Gebäude D3), D-48149 Münster, Germany.
4
Department of Drug Design and Pharmacology (Center for Biopharmaceuticals), University of Copenhagen, Jagtvej 160, DK-2100 Copenhagen, Denmark.

Abstract

Retigabine is a recently approved anticonvulsant that acts by potentiating neuronal M-current generated by KCNQ2-5 channels, interacting with a conserved Trp residue in the channel pore domain. Using unnatural amino-acid mutagenesis, we subtly altered the properties of this Trp to reveal specific chemical interactions required for retigabine action. Introduction of a non-natural isosteric H-bond-deficient Trp analogue abolishes channel potentiation, indicating that retigabine effects rely strongly on formation of a H-bond with the conserved pore Trp. Supporting this model, substitution with fluorinated Trp analogues, with increased H-bonding propensity, strengthens retigabine potency. In addition, potency of numerous retigabine analogues correlates with the negative electrostatic surface potential of a carbonyl/carbamate oxygen atom present in most KCNQ activators. These findings functionally pinpoint an atomic-scale interaction essential for effects of retigabine and provide stringent constraints that may guide rational improvement of the emerging drug class of KCNQ channel activators.

PMID:
26333338
PMCID:
PMC4561856
DOI:
10.1038/ncomms9116
[Indexed for MEDLINE]
Free PMC Article

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