Back to Search
Start Over
A specific two-pore domain potassium channel blocker defines the structure of the TASK-1 open pore.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2011 Apr 22; Vol. 286 (16), pp. 13977-84. Date of Electronic Publication: 2011 Mar 01. - Publication Year :
- 2011
-
Abstract
- Two-pore domain potassium (K(2P)) 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 K(2P) channels. We describe A1899 as a potent and highly selective blocker of the K(2P) 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 K(2P) open-pore homology model of TASK-1, providing structural insights for future rational design of drugs targeting K(2P) channels.
- Subjects :
- Alanine chemistry
Animals
Benzamides chemistry
Benzeneacetamides chemistry
Binding Sites
DNA, Complementary metabolism
Drug Design
Humans
Inhibitory Concentration 50
Models, Molecular
Mutagenesis
Mutagenesis, Site-Directed
Oocytes cytology
Patch-Clamp Techniques
Protein Conformation
Xenopus laevis
Benzamides pharmacology
Benzeneacetamides pharmacology
Nerve Tissue Proteins chemistry
Potassium chemistry
Potassium Channel Blockers pharmacology
Potassium Channels, Tandem Pore Domain chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 286
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 21362619
- Full Text :
- https://doi.org/10.1074/jbc.M111.227884