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\begin{document}

\title{Tricyclic antipsychotics and antidepressants can inhibit \selectlanguage{greek}α\selectlanguage{english}5-containing
GABA\textsubscript{A} receptors by two~ distinct mechanisms~~~~~~~~~~~~\selectlanguage{english}}



\author[1]{Konstantina Bampali}%
\author[1]{Filip Koniuszewski}%
\author[1]{Luca Silva}%
\author[1]{Sabah Rehman}%
\author[1]{Florian Vogel}%
\author[2]{Thomas Seidel}%
\author[1]{Petra Scholze}%
\author[1]{Florian Zirpel}%
\author[2]{Arthur Garon}%
\author[2]{Thierry Langer}%
\author[1]{Matthäus Willeit}%
\author[1]{Margot Ernst}%
\affil[1]{Medical University of Vienna}%
\affil[2]{University of Vienna}%


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  \date{June 08, 2024}


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\begin{abstract}
\textbf{Background and Purpose:} Many psychotherapeutic drugs, including
clozapine, display polypharmacology and act on GABA\textsubscript{A}
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
GABA\textsubscript{A} receptors. The purpose of this study is to
investigate tricyclic compounds in a5 subunit-containing receptor
subtypes.

\textbf{Experimental Approach:} Functional studies of effects by seven
antipsychotic and antidepressant medications were performed in several
GABA\textsubscript{A} receptor subtypes by two-electrode voltage-clamp
electrophysiology using \emph{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.

\textbf{Key Results:} We show that the antipsychotic drugs clozapine and
chlorpromazine exert functional inhibition on multiple
GABA\textsubscript{A} 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
GABA\textsubscript{A} receptor subunits and demonstrate differential
usage of this and the orthosteric sites by these ligands.

\textbf{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 GABA\textsubscript{A} receptor subtypes.%
\end{abstract}%



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