Atomic basis for therapeutic activation of neuronal potassium channels
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Atomic basis for therapeutic activation of neuronal potassium channels. / Kim, Robin Y; Yau, Michael C; Galpin, Jason D; Seebohm, Guiscard; Ahern, Christopher A; Pless, Stephan A; Kurata, Harley T.
In: Nature Communications, Vol. 6, 8116, 2015, p. 1-11.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Atomic basis for therapeutic activation of neuronal potassium channels
AU - Kim, Robin Y
AU - Yau, Michael C
AU - Galpin, Jason D
AU - Seebohm, Guiscard
AU - Ahern, Christopher A
AU - Pless, Stephan A
AU - Kurata, Harley T
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
U2 - 10.1038/ncomms9116
DO - 10.1038/ncomms9116
M3 - Journal article
C2 - 26333338
VL - 6
SP - 1
EP - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 8116
ER -
ID: 157061886