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Identification of amino acid residues responsible for the α5 subunit binding selectivity of L‐655,708, a benzodiazepine binding site ligand at the GABA A receptor
Author(s) -
Casula M. Anna,
Bromidge Frances A.,
Pillai Gopalan V.,
Wingrove Peter B.,
Martin Karine,
Maubach Karen,
Seabrook Guy R.,
Whiting Paul J.,
Hadingham Karen L.
Publication year - 2001
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 - 10.1046/j.1471-4159.2001.00289.x
Subject(s) - receptor , binding site , gabaa receptor , amino acid , ligand (biochemistry) , transmembrane domain , chemistry , binding selectivity , protein subunit , biochemistry , agonist , stereochemistry , biology , gene
L‐655,708 is a ligand for the benzodiazepine site of the γ‐aminobutyric acid type A (GABA A ) receptor that exhibits a 100‐fold higher affinity for α5‐containing receptors compared with α1‐containing receptors. Molecular biology approaches have been used to determine which residues in the α5 subunit are responsible for this selectivity. Two amino acids have been identified, α5Thr208 and α5Ile215, each of which individually confer approximately 10‐fold binding selectivity for the ligand and which together account for the 100‐fold higher affinity of this ligand at α5‐containing receptors. L‐655,708 is a partial inverse agonist at the GABA A receptor which exhibited no functional selectivity between α1‐ and α5‐containing receptors and showed no change in efficacy at receptors containing α1 subunits where amino acids at both of the sites had been altered to their α5 counterparts (α1ΔSer205‐Thr,Val212‐Ile). In addition to determining the binding selectivity of L‐655,708, these amino acid residues also influence the binding affinities of a number of other benzodiazepine (BZ) site ligands. They are thus important elements of the BZ site of the GABA A receptor, and further delineate a region just N‐terminal to the first transmembrane domain of the receptor α subunit that contributes to this binding site.