RGD Reference Report - A single histidine in GABAA receptors is essential for benzodiazepine agonist binding. - Rat Genome Database

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A single histidine in GABAA receptors is essential for benzodiazepine agonist binding.

Authors: Wieland, HA  Luddens, H  Seeburg, PH 
Citation: Wieland HA, etal., J Biol Chem 1992 Jan 25;267(3):1426-9.
RGD ID: 728715
Pubmed: PMID:1346133   (View Abstract at PubMed)

Benzodiazepines (BZ) modulate neurotransmitter-evoked chloride currents at the gamma-aminobutyric acid type A (GABAA) receptor, the major inhibitory ion channel in the mammalian brain. This receptor is composed of structurally distinct subunits whose numerous molecular variants underlie the observed diversity in the properties of the BZ site. Pharmacologically distinct BZ sites can be recreated by the recombinant coexpression of any one of six alpha subunits, a beta subunit variant, and the gamma 2 subunit. In these receptors the alpha variant determines the affinity for ligand binding of the BZ site. Notably, the alpha 1 and alpha 6 variants impart on alpha chi beta 2 gamma 2 receptors high and negligible affinity, respectively, to BZ ligands with sedative as well as anxiolytic activities. By exchanging domains between the alpha 1 and alpha 6 variants, we show that a portion of the large extracellular domain determines sensitivity toward these ligands. Furthermore, we identify a single histidine residue in the alpha 1 variant, replaced by an arginine in alpha 6, as a major determinant for high affinity binding of BZ agonists. This residue also plays a role in determining high affinity binding for BZ antagonists. Hence, this histidine present in the alpha 1, alpha 2, alpha 3, and alpha 5 subunits appears to be a key residue for the action of clinically used BZ ligands.



Gene-Chemical Interaction Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
GABRA1Humandiazepam affects bindingISOGabra1 (Rattus norvegicus)Diazepam binds to Gabra1 proteinRGD 
Gabra1Ratdiazepam affects bindingEXP Diazepam binds to Gabra1 proteinRGD 
Gabra1Mousediazepam affects bindingISOGabra1 (Rattus norvegicus)Diazepam binds to Gabra1 proteinRGD 
GABRA1Humanflumazenil affects bindingISOGabra1 (Rattus norvegicus)Flumazenil binds to Gabra1 proteinRGD 
Gabra1Ratflumazenil affects bindingEXP Flumazenil binds to Gabra1 proteinRGD 
Gabra1Mouseflumazenil affects bindingISOGabra1 (Rattus norvegicus)Flumazenil binds to Gabra1 proteinRGD 
GABRA1Humanzolpidem affects bindingISOGabra1 (Rattus norvegicus)Zolpidem binds to Gabra1 proteinRGD 
Gabra1Ratzolpidem affects bindingEXP Zolpidem binds to Gabra1 proteinRGD 
Gabra1Mousezolpidem affects bindingISOGabra1 (Rattus norvegicus)Zolpidem binds to Gabra1 proteinRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Gabra1Ratdiazepam binding  IDA  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Gabra1  (gamma-aminobutyric acid type A receptor subunit alpha 1)

Genes (Mus musculus)
Gabra1  (gamma-aminobutyric acid type A receptor subunit alpha 1)

Genes (Homo sapiens)
GABRA1  (gamma-aminobutyric acid type A receptor subunit alpha1)


Additional Information