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Tricyclic antipsychotics and antidepressants can inhibit α5-containing GABAA receptors by two  distinct mechanisms            
  • +9
  • Konstantina Bampali,
  • Filip Koniuszewski,
  • Luca Silva,
  • Sabah Rehman,
  • Florian Vogel,
  • Thomas Seidel,
  • Petra Scholze,
  • Florian Zirpel,
  • Arthur Garon,
  • Thierry Langer,
  • Matthäus Willeit,
  • Margot Ernst
Konstantina Bampali
Medical University of Vienna

Corresponding Author:[email protected]

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Filip Koniuszewski
Medical University of Vienna
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Luca Silva
Medical University of Vienna
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Sabah Rehman
Medical University of Vienna
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Florian Vogel
Medical University of Vienna
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Thomas Seidel
University of Vienna
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Petra Scholze
Medical University of Vienna
Florian Zirpel
Medical University of Vienna
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Arthur Garon
University of Vienna
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Thierry Langer
University of Vienna
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Matthäus Willeit
Medical University of Vienna
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Margot Ernst
Medical University of Vienna
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Abstract

Background and Purpose: Many psychotherapeutic drugs, including clozapine, display polypharmacology and act on GABAA receptors. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal a5 subunit-containing GABAA receptors. The purpose of this study is to investigate tricyclic compounds in a5 subunit-containing receptor subtypes.
Experimental Approach: Functional studies of effects by seven antipsychotic and antidepressant medications were performed in several GABAA receptor subtypes by two‐electrode voltage‐clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the a5 subunit, probing a novel binding site. Radioligand displacement data complemented the functional and mutational findings.
Key Results: We show that the antipsychotic drugs clozapine and chlorpromazine exert functional inhibition on multiple GABAA receptor subtypes, including a5-containing ones. Based on a chlorpromazine binding site observed in a GABA-gated bacterial homologue, we identified a novel site in a5 GABAA receptor subunits and demonstrate differential usage of this and the orthosteric sites by these ligands.
Conclusion and Implications: Despite high molecular and functional similarities among the tested ligands, they reduce GABA currents by differential usage of allosteric and orthosteric sites. The C C C C C C site we describe here is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology. Further studies in defined subtypes are needed to substantiate mechanistic links between the therapeutic effects of clozapine and its action on certain GABAA receptor subtypes.
06 Apr 2021Submitted to British Journal of Pharmacology
06 Apr 2021Submission Checks Completed
06 Apr 2021Assigned to Editor
09 Apr 2021Reviewer(s) Assigned
09 May 2021Review(s) Completed, Editorial Evaluation Pending
10 May 2021Editorial Decision: Revise Minor
20 Aug 20211st Revision Received
23 Aug 2021Submission Checks Completed
23 Aug 2021Assigned to Editor
24 Aug 2021Reviewer(s) Assigned
13 Sep 2021Review(s) Completed, Editorial Evaluation Pending
14 Sep 2021Editorial Decision: Revise Minor
10 Dec 20212nd Revision Received
14 Dec 2021Submission Checks Completed
14 Dec 2021Assigned to Editor
17 Dec 2021Reviewer(s) Assigned
10 Jan 2022Review(s) Completed, Editorial Evaluation Pending
12 Jan 2022Editorial Decision: Accept