Atomic basis for therapeutic activation of neuronal potassium channels

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

doi:10.1038/ncomms9116

Back

Atomic basis for therapeutic activation of neuronal potassium channels

Journal article

Open access

Peer reviewed

Atomic basis for therapeutic activation of neuronal potassium channels

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

Nature communications, Vol.6(1), pp.8116-8116

09/03/2015

DOI: 10.1038/ncomms9116

PMCID: PMC4561856

PMID: 26333338

Files and links (1)

url

https://doi.org/10.1038/ncomms9116View

Published (Version of record) Open Access

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.

Humans

KCNQ3 Potassium Channel - drug effects

KCNQ2 Potassium Channel - drug effects

Anticonvulsants - pharmacology

Phenylenediamines - metabolism

Tryptophan - metabolism

Carbamates - metabolism

Fluorine - metabolism

KCNQ2 Potassium Channel - metabolism

Oocytes - drug effects

Neurons - metabolism

Neurons - drug effects

Carbamates - pharmacology

Mutagenesis, Site-Directed

KCNQ3 Potassium Channel - metabolism

Oocytes - metabolism

Xenopus laevis

Anticonvulsants - metabolism

KCNQ3 Potassium Channel - genetics

KCNQ Potassium Channels - drug effects

Patch-Clamp Techniques

Animals

Hydrogen Bonding

KCNQ Potassium Channels - metabolism

KCNQ2 Potassium Channel - genetics

Phenylenediamines - pharmacology

Molecular Docking Simulation

KCNQ Potassium Channels - genetics

Details

Title: Subtitle: Atomic basis for therapeutic activation of neuronal potassium channels
Creators: Robin Y Kim - Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3
Michael C Yau - Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3
Jason D Galpin - Department of Molecular Physiology and Biophysics, University of Iowa, 285 Newton Road, Iowa City, Iowa 52242, USA
Guiscard Seebohm - Department of Cardiovascular Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1 (Gebäude D3), D-48149 Münster, Germany
Christopher A Ahern - Department of Molecular Physiology and Biophysics, University of Iowa, 285 Newton Road, Iowa City, Iowa 52242, USA
Stephan A Pless - Department of Drug Design and Pharmacology (Center for Biopharmaceuticals), University of Copenhagen, Jagtvej 160, DK-2100 Copenhagen, Denmark
Harley T Kurata - Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3
Resource Type: Journal article
Publication Details: Nature communications, Vol.6(1), pp.8116-8116
DOI: 10.1038/ncomms9116
PMID: 26333338
PMCID: PMC4561856
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Publisher: England
Grant note: MOP-97988 / Canadian Institutes of Health Research GM106569 / NIGMS NIH HHS U54 GM087519 / NIGMS NIH HHS GM087519 / NIGMS NIH HHS R01 GM106569 / NIGMS NIH HHS
Language: English
Date published: 09/03/2015
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute
Record Identifier: 9984065483702771

Metrics

40 Record Views

76 Times Cited - Web of Science

See more details