Unique effect of clozapine on adenosine A 2A -dopamine D 2 receptor heteromerization.

Autor: Valle-León M; Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907 L'Hospitalet de Llobregat, Spain; Neuropharmacology and Pain Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, 08907 L'Hospitalet de Llobregat, Spain., Casajuana-Martin N; Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Universitat Autònoma Barcelona, Bellaterra, 08193 Barcelona, Spain., Del Torrent CL; Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Universitat Autònoma Barcelona, Bellaterra, 08193 Barcelona, Spain., Argerich J; Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907 L'Hospitalet de Llobregat, Spain; Neuropharmacology and Pain Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, 08907 L'Hospitalet de Llobregat, Spain., Gómez-Acero L; Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907 L'Hospitalet de Llobregat, Spain; Neuropharmacology and Pain Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, 08907 L'Hospitalet de Llobregat, Spain., Sahlholm K; Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907 L'Hospitalet de Llobregat, Spain; Neuropharmacology and Pain Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, 08907 L'Hospitalet de Llobregat, Spain; Department of Integrative Medical Biology, Wallenberg Centre for Molecular Medicine, Umeå University, 907 87 Umeå, Sweden; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden., Ferré S; Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA. Electronic address: sferre@intra.nida.nih.gov., Pardo L; Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Universitat Autònoma Barcelona, Bellaterra, 08193 Barcelona, Spain. Electronic address: leonardo.pardo@uab.cat., Ciruela F; Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907 L'Hospitalet de Llobregat, Spain; Neuropharmacology and Pain Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, 08907 L'Hospitalet de Llobregat, Spain. Electronic address: fciruela@ub.edu.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2023 Apr; Vol. 160, pp. 114327. Date of Electronic Publication: 2023 Feb 01.
DOI: 10.1016/j.biopha.2023.114327
Abstrakt: The striatal dopamine D 2 receptor (D 2 R) is generally accepted to be involved in positive symptoms of schizophrenia and is a main target for clinically used antipsychotics. D 2 R are highly expressed in the striatum, where they form heteromers with the adenosine A 2A receptor (A 2A R). Changes in the density of A 2A R-D 2 R heteromers have been reported in postmortem tissue from patients with schizophrenia, but the degree to which A 2 R are involved in schizophrenia and the effect of antipsychotic drugs is unknown. Here, we examine the effect of exposure to three prototypical antipsychotic drugs on A 2A R-D 2 R heteromerization in mammalian cells using a NanoBiT assay. After 16 h of exposure, a significant increase in the density of A 2A R-D 2 R heteromers was found with haloperidol and aripiprazole, but not with clozapine. On the other hand, clozapine, but not haloperidol or aripiprazole, was associated with a significant decrease in A 2A R-D 2 R heteromerization after 2 h of treatment. Computational binding models of these compounds revealed distinctive molecular signatures that explain their different influence on heteromerization. The bulky tricyclic moiety of clozapine displaces TM 5 of D 2 R, inducing a clash with A 2A R, while the extended binding mode of haloperidol and aripiprazole stabilizes a specific conformation of the second extracellular loop of D 2 R that enhances the interaction with A 2A R. It is proposed that an increase in A 2A R-D 2 R heteromerization is involved in the extrapyramidal side effects (EPS) of antipsychotics and that the specific clozapine-mediated destabilization of A 2A R-D 2 R heteromerization can explain its low EPS liability.
Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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