1. A histidine residue in the N-terminal extracellular region of alpha 1,2,3,5 subunits of the @entity1 GABA(A) receptor, which is replaced by an arginine in alpha 4 and alpha 6 subunits, is a major determinant for high affinity binding of classical benzodiazepine (BZ)-site ligands. The effect of mutating this histidine at position 105 in the alpha 5 subunit to an arginine (alpha 5 @entity32321 ) on BZ-site pharmacology has been investigated using radioligand binding on HEK293 and L(tk-) cells and two electrode voltage clamp recording on @entity1238 oocytes in which GABA(A) receptors of subtypes alpha 5, alpha 5 @entity32321 , alpha 4 and alpha 6 were co-expressed with beta 3 gamma 2s. 2. The classical BZs, diazepam and flunitrazepam (full agonists on the alpha 5 receptor) showed negligible affinity and therefore negligible efficacy on alpha 5H105R receptors. The beta-carbolines DMCM and beta CCE (inverse agonists on the alpha 5 receptor) retained some affinity but did not exhibit inverse agonist efficacy at alpha 5H105R receptors. Therefore, the alpha 5 @entity32321 mutation confers an alpha 4/alpha 6-like pharmacology to the classical BZs and beta-carbolines. 3. Ro15-4513, flumazenil, bretazenil and FG8094, which share a common imidazobenzodiazepine core structure, retained high affinity and were higher efficacy agonists on alpha 5H105R receptors than would be predicted from an alpha 4/alpha 6 pharmacological profile. This effect was antagonized by DMCM, which competes for the BZ-site and therefore is likely to be mediated via the BZ-site. 4. These data indicate that the conserved histidine residue in the alpha subunit is not only a key determinant in the affinity of BZ-site ligands on alpha 5 containing GABA(A) receptors, but also influences ligand efficacy.

Role of the histidine residue at position 105 in the XXXX alpha 5 containing GABA(A) receptor on the affinity and efficacy of benzodiazepine site ligands.

@entity1 :: ('9606', 'Species') :: ['human'] @entity32321 :: ('p|SUB|H|105|R', 'ProteinMutation') :: ['H105R'] @entity1238 :: ('8355', 'Species') :: ['Xenopus']
@entity1 :: (9606,Species) :: ['human']
