Atomic basis for therapeutic activation of neuronal potassium channels

Research output: Contribution to journal › Journal article › Research › peer-review

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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

Harvard

Kim, RY, Yau, MC, Galpin, JD, Seebohm, G, Ahern, CA, Pless, SA & Kurata, HT 2015, 'Atomic basis for therapeutic activation of neuronal potassium channels', Nature Communications, vol. 6, 8116, pp. 1-11. https://doi.org/10.1038/ncomms9116

APA

Kim, R. Y., Yau, M. C., Galpin, J. D., Seebohm, G., Ahern, C. A., Pless, S. A., & Kurata, H. T. (2015). Atomic basis for therapeutic activation of neuronal potassium channels. Nature Communications, 6, 1-11. [8116]. https://doi.org/10.1038/ncomms9116

Vancouver

Kim RY, Yau MC, Galpin JD, Seebohm G, Ahern CA, Pless SA et al. Atomic basis for therapeutic activation of neuronal potassium channels. Nature Communications. 2015;6:1-11. 8116. https://doi.org/10.1038/ncomms9116

Author

Kim, Robin Y ; Yau, Michael C ; Galpin, Jason D ; Seebohm, Guiscard ; Ahern, Christopher A ; Pless, Stephan A ; Kurata, Harley T. / Atomic basis for therapeutic activation of neuronal potassium channels. In: Nature Communications. 2015 ; Vol. 6. pp. 1-11.

Bibtex

@article{3ff1179a141b40e7bb139a9b3ab7cf44,
title = "Atomic basis for therapeutic activation of neuronal potassium channels",
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.",
author = "Kim, {Robin Y} and Yau, {Michael C} and Galpin, {Jason D} and Guiscard Seebohm and Ahern, {Christopher A} and Pless, {Stephan A} and Kurata, {Harley T}",
year = "2015",
doi = "10.1038/ncomms9116",
language = "English",
volume = "6",
pages = "1--11",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "nature publishing group",

}

RIS

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