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Atomic basis for therapeutic activation of neuronal potassium channels

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Robin Y Kim
  • Michael C Yau
  • Jason D Galpin
  • Guiscard Seebohm
  • Christopher A Ahern
  • Pless, Stephan
  • Harley T Kurata

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.

OriginalsprogEngelsk
Artikelnummer8116
TidsskriftNature Communications
Vol/bind6
Sider (fra-til)1-11
Antal sider11
ISSN2041-1723
DOI
StatusUdgivet - 2015

ID: 157061886