? subunits in GABAA receptors are dispensable for GABA and diazepam action.

ABSTRACT: The major isoform of the GABAA receptor is ?1?2?2. The binding sites for the agonist GABA are located at the ?2+/?1- subunit interfaces and the modulatory site for benzodiazepines at ?1+/?2-. In the absence of ?1 subunits, a receptor was formed that was gated by GABA and modulated by diazepam similarly. This indicates that alternative subunits can take over the role of the ?1 subunits. Point mutations were introduced in ?2 or ?2 subunits at positions homologous to ?1- benzodiazepine binding and GABA binding positions, respectively. From this mutation work we conclude that the site for GABA is located at a ?2+/?2- subunit interface and that the diazepam site is located at the ?2+/?2- subunit interface. Computational docking leads to a structural hypothesis attributing this non-canonical interaction to a binding mode nearly identical with the one at the ?1+/?2- interface. Thus, the ?2 subunit can take over the role of the ?1 subunit for the formation of both sites, its minus side for the GABA binding site and its plus side for the diazepam binding site.

SUBMITTER: Wongsamitkul N 

PROVIDER: S-EPMC5686171 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature