Atomic basis for therapeutic activation of neuronal potassium channels

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticonvulsants / metabolism
  • Anticonvulsants / pharmacology*
  • Carbamates / metabolism
  • Carbamates / pharmacology*
  • Fluorine / metabolism
  • Humans
  • Hydrogen Bonding
  • KCNQ Potassium Channels / drug effects*
  • KCNQ Potassium Channels / genetics
  • KCNQ Potassium Channels / metabolism
  • KCNQ2 Potassium Channel / drug effects
  • KCNQ2 Potassium Channel / genetics
  • KCNQ2 Potassium Channel / metabolism
  • KCNQ3 Potassium Channel / drug effects
  • KCNQ3 Potassium Channel / genetics
  • KCNQ3 Potassium Channel / metabolism
  • Molecular Docking Simulation
  • Mutagenesis, Site-Directed
  • Neurons / drug effects*
  • Neurons / metabolism
  • Oocytes / drug effects
  • Oocytes / metabolism
  • Patch-Clamp Techniques
  • Phenylenediamines / metabolism
  • Phenylenediamines / pharmacology*
  • Tryptophan / metabolism
  • Xenopus laevis

Substances

  • Anticonvulsants
  • Carbamates
  • KCNQ Potassium Channels
  • KCNQ2 Potassium Channel
  • KCNQ2 protein, human
  • KCNQ3 Potassium Channel
  • KCNQ3 protein, human
  • Phenylenediamines
  • ezogabine
  • Fluorine
  • Tryptophan