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

Atomic basis for therapeutic activation of neuronal potassium channels.

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


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.

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