A Specific Two-pore Domain Potassium Channel Blocker Defines the Structure of the TASK-1 Open Pore

Two-pore domain potassium (K2P) channels play a key role in setting the membrane potential of excitable cells. Despite their role as putative targets for drugs and general anesthetics, little is known about the structure and the drug binding site of K2P channels. We describe A1899 as a potent and hi...

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Bibliographic Details
Published in:The Journal of biological chemistry 2011-04, Vol.286 (16), p.13977-13984
Main Authors: Streit, Anne K., Netter, Michael F., Kempf, Franca, Walecki, Magdalena, Rinné, Susanne, Bollepalli, Murali K., Preisig-Müller, Regina, Renigunta, Vijay, Daut, Jürgen, Baukrowitz, Thomas, Sansom, Mark S.P., Stansfeld, Phillip J., Decher, Niels
Format: Article
Language:English
Subjects:
Alanine - chemistry
Animals
Benzamides - chemistry
Benzamides - pharmacology
Benzeneacetamides - chemistry
Benzeneacetamides - pharmacology
Binding Sites
DNA, Complementary - metabolism
Drug Design
Humans
Inhibitory Concentration 50
ion Channel Blocker
Ion Channels
Models, Molecular
Molecular Dynamics
Mutagenesis
Mutagenesis, Site-Directed
Nerve Tissue Proteins - chemistry
Oocytes - cytology
Patch-Clamp Techniques
Potassium - chemistry
Potassium Channel Blockers - pharmacology
Potassium Channels
Potassium Channels, Tandem Pore Domain - chemistry
Protein Conformation
Protein Structure and Folding
Xenopus laevis
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Summary:Two-pore domain potassium (K2P) channels play a key role in setting the membrane potential of excitable cells. Despite their role as putative targets for drugs and general anesthetics, little is known about the structure and the drug binding site of K2P channels. We describe A1899 as a potent and highly selective blocker of the K2P channel TASK-1. As A1899 acts as an open-channel blocker and binds to residues forming the wall of the central cavity, the drug was used to further our understanding of the channel pore. Using alanine mutagenesis screens, we have identified residues in both pore loops, the M2 and M4 segments, and the halothane response element to form the drug binding site of TASK-1. Our experimental data were used to validate a K2P open-pore homology model of TASK-1, providing structural insights for future rational design of drugs targeting K2P channels.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M111.227884