Atomic basis for therapeutic activation of neuronal potassium channels
By Robin Y. Kim, Michael C. Yau, Jason D. Galpin, Guiscard Seebohm, Christopher A Ahern, Stephen Pless and Harley Kutara.
Published in Nature Communications 2915 Sep 3;6:8116.
PMID: 26333338. PMCID: PMC4561856. Link to Pubmed page.
Core Facility: Membrane Protein Expression/Purification.
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.