loading page

Interactions of tricyclic antipsychotic and antidepressant medications with a novel binding site in GABAA receptors
  • +8
  • Konstantina Bampali,
  • Filip Koniuszewski,
  • Luca Silva,
  • Sabah Rehman,
  • Florian Vogel,
  • Thomas Seidel,
  • Florian Zirpel,
  • Arthur Garon,
  • Thierry Langer,
  • Matthäus Willeit,
  • Margot Ernst
Konstantina Bampali
Medical University of Vienna
Author Profile
Filip Koniuszewski
Medical University of Vienna
Author Profile
Luca Silva
Medical University of Vienna
Author Profile
Sabah Rehman
Medical University of Vienna
Author Profile
Florian Vogel
Medical University of Vienna
Author Profile
Thomas Seidel
University of Vienna
Author Profile
Florian Zirpel
Medical University of Vienna
Author Profile
Arthur Garon
University of Vienna
Author Profile
Thierry Langer
University of Vienna
Author Profile
Matthäus Willeit
Medical University of Vienna
Author Profile
Margot Ernst
Medical University of Vienna
Author Profile

Abstract

Background and Purpose: Many psychotherapeutic drugs including clozapine have a polypharmacological profile and act on GABAA receptors, where subtype-specific information is often lacking. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal α5 subunit containing GABAA receptors. Experimental Approach: Functional studies of GABA modulatory effects by 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 α5 subunit, probing a novel binding site. Computational ligand analysis complemented the functional and mutational data. Key Results: We show that the antipsychotic drugs clozapine and chlorpromazine have negative modulatory effects on multiple GABAA receptor subtypes, including α5-containing. On the latter we show negative modulatory effects for five additional antipsychotic and antidepressant drugs. Based on a chlorpromazine binding site observed in a GABA-gated bacterial homologue, we identified a novel site in α5 GABAA receptor subunits. Conclusion and Implications: Our findings support previous studies suggesting a link between some of the therapeutic effects of clozapine and its negative modulatory action on certain GABAA receptor subtypes. The novel site we describe in this study is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology.

Peer review status:IN REVISION

06 Apr 2021Submitted to British Journal of Pharmacology
06 Apr 2021Assigned to Editor
06 Apr 2021Submission Checks Completed
09 Apr 2021Reviewer(s) Assigned
09 May 2021Review(s) Completed, Editorial Evaluation Pending
10 May 2021Editorial Decision: Revise Minor