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? 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

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

Wongsamitkul Nisa N Maldifassi Maria C MC Simeone Xenia X Baur Roland R Ernst Margot M Sigel Erwin E

Scientific reports 20171114 1

The major isoform of the GABAA receptor is α1β2γ2. The binding sites for the agonist GABA are located at the β2+/α1- subunit interfaces and the modulatory site for benzodiazepines at α1+/γ2-. In the absence of α1 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 α1 subunits. P ...[more]

PMID: 29138471

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Project description:BackgroundWithin the GABA(A)-receptor field, two important questions are what molecular mechanisms underlie benzodiazepine tolerance, and whether tolerance can be ascribed to certain GABA(A)-receptor subtypes.MethodsWe investigated tolerance to acute anxiolytic, hypothermic and sedative effects of diazepam in mice exposed for 28-days to non-selective/selective GABA(A)-receptor positive allosteric modulators: diazepam (non-selective), bretazenil (partial non-selective), zolpidem (?(1) selective) and TPA023 (?(2/3) selective). In-vivo binding studies with [(3)H]flumazenil confirmed compounds occupied CNS GABA(A) receptors.ResultsChronic diazepam treatment resulted in tolerance to diazepam's acute anxiolytic, hypothermic and sedative effects. In mice treated chronically with bretazenil, tolerance to diazepam's anxiolytic and hypothermic, but not sedative, effects was seen. Chronic zolpidem treatment resulted in tolerance to diazepam's hypothermic effect, but partial anxiolytic tolerance and no sedative tolerance. Chronic TPA023 treatment did not result in tolerance to diazepam's hypothermic, anxiolytic or sedative effects.ConclusionsOUR DATA INDICATE THAT: (i) GABA(A)-?(2)/?(3) subtype selective drugs might not induce tolerance; (ii) in rodents quantitative and temporal variations in tolerance development occur dependent on the endpoint assessed, consistent with clinical experience with benzodiazepines (e.g., differential tolerance to antiepileptic and anxiolytic actions); (iii) tolerance to diazepam's sedative actions needs concomitant activation of GABA(A)-?(1)/GABA(A)-?(5) receptors. Regarding mechanism, in-situ hybridization studies indicated no gross changes in expression levels of GABA(A) ?(1), ?(2) or ?(5) subunit mRNA in hippocampus or cortex. Since selective chronic activation of either GABA(A) ?(2), or ?(3) receptors does not engender tolerance development, subtype-selective GABA(A) drugs might constitute a promising class of novel drugs.

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

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α subunits in GABA<sub>A</sub> receptors are dispensable for GABA and diazepam action.

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

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α subunits in GABA&lt;sub&gt;A&lt;/sub&gt; receptors are dispensable for GABA and diazepam action.

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OmicsDI is part of the ELIXIR infrastructure

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α subunits in GABA<sub>A</sub> receptors are dispensable for GABA and diazepam action.