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Molecular analysis of the site for 2‐arachidonylglycerol (2‐ AG ) on the β 2 subunit of GABA A receptors
Author(s) -
Baur Roland,
Kielar Marie,
Richter Lars,
Ernst Margot,
Ecker Gerhard F.,
Sigel Erwin
Publication year - 2013
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12270
Subject(s) - protein subunit , transmembrane domain , chemistry , helix (gastropod) , ligand (biochemistry) , receptor , stereochemistry , allosteric regulation , cysteine , gabaa receptor , transmembrane protein , binding site , molecule , biophysics , biochemistry , biology , enzyme , snail , ecology , organic chemistry , gene
2‐arachidonyl glycerol (2‐AG) allosterically potentiates GABA A receptors via a binding site located in transmembrane segment M4 of the β 2 subunit. Two amino acid residues have been described that are essential for this effect. With the aim to further describe this potential drug target, we performed a cysteine scanning of the entire M4 and part of M3. All four residues in M4 affecting the potentiation here and the two already identified residues locate to the same side of the α‐helix. This side is exposed to M3, where further residues were identified. From the fact that the important residues span > 18 Å, we conclude that the hydrophobic tail of the bound 2‐ AG molecule must be near linear and that the site mainly locates to the inner leaflet but stretches far into the membrane. The influence of the structure of the head group of the ligand molecule on the activity of the molecule was also investigated. We present a model of 2‐ AG docked to the GABA A receptor.