Unique effect of clozapine on adenosine A2A-dopamine D2 receptor heteromerization

The striatal dopamine D2 receptor (D2R) is generally accepted to be involved in positive symptoms of schizophrenia and is a main target for clinically used antipsychotics. D2R are highly expressed in the striatum, where they form heteromers with the adenosine A2A receptor (A2AR). Changes in the dens...

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Autores: Valle León, Marta, Casajuana-Martin, Nil, Llinàs del Torrent, Clàudia, Argerich, Josep, Gómez Acero, Laura, Sahlholm, Kristoffer, Ferré, Sergi, Pardo, Leonardo, Ciruela Alférez, Francisco
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/198681
Acceso en línea:https://hdl.handle.net/2445/198681
Access Level:acceso abierto
Palabra clave:Adenosina
Dopamina
Antipsicòtics
Adenosine
Dopamine
Antipsychotic drugs
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spelling Unique effect of clozapine on adenosine A2A-dopamine D2 receptor heteromerizationValle León, MartaCasajuana-Martin, NilLlinàs del Torrent, ClàudiaArgerich, JosepGómez Acero, LauraSahlholm, KristofferFerré, SergiPardo, LeonardoCiruela Alférez, FranciscoAdenosinaDopaminaAntipsicòticsAdenosineDopamineAntipsychotic drugsThe striatal dopamine D2 receptor (D2R) is generally accepted to be involved in positive symptoms of schizophrenia and is a main target for clinically used antipsychotics. D2R are highly expressed in the striatum, where they form heteromers with the adenosine A2A receptor (A2AR). Changes in the density of A2AR-D2R heteromers have been reported in postmortem tissue from patients with schizophrenia, but the degree to which A2R 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 A2AR-D2R heteromerization in mammalian cells using a NanoBiT assay. After 16 h of exposure, a significant increase in the density of A2AR-D2R 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 A2AR-D2R 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 D2R, inducing a clash with A2AR, while the extended binding mode of haloperidol and aripiprazole stabilizes a specific conformation of the second extracellular loop of D2R that enhances the interaction with A2AR. It is proposed that an increase in A2AR-D2R heteromerization is involved in the extrapyramidal side effects (EPS) of antipsychotics and that the specific clozapine-mediated destabilization of A2AR-D2R heteromerization can explain its low EPS liability.Elsevier Masson SAS2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/198681Articles publicats en revistes (Patologia i Terapèutica Experimental)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1016/j.biopha.2023.114327Biomedicine & Pharmacotherapy, 2023, vol. 160, p. 114327https://doi.org/10.1016/j.biopha.2023.114327cc by-nc-nd (c) Valle León, Marta et al., 2023https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1986812026-05-27T06:46:51Z
dc.title.none.fl_str_mv Unique effect of clozapine on adenosine A2A-dopamine D2 receptor heteromerization
title Unique effect of clozapine on adenosine A2A-dopamine D2 receptor heteromerization
spellingShingle Unique effect of clozapine on adenosine A2A-dopamine D2 receptor heteromerization
Valle León, Marta
Adenosina
Dopamina
Antipsicòtics
Adenosine
Dopamine
Antipsychotic drugs
title_short Unique effect of clozapine on adenosine A2A-dopamine D2 receptor heteromerization
title_full Unique effect of clozapine on adenosine A2A-dopamine D2 receptor heteromerization
title_fullStr Unique effect of clozapine on adenosine A2A-dopamine D2 receptor heteromerization
title_full_unstemmed Unique effect of clozapine on adenosine A2A-dopamine D2 receptor heteromerization
title_sort Unique effect of clozapine on adenosine A2A-dopamine D2 receptor heteromerization
dc.creator.none.fl_str_mv Valle León, Marta
Casajuana-Martin, Nil
Llinàs del Torrent, Clàudia
Argerich, Josep
Gómez Acero, Laura
Sahlholm, Kristoffer
Ferré, Sergi
Pardo, Leonardo
Ciruela Alférez, Francisco
author Valle León, Marta
author_facet Valle León, Marta
Casajuana-Martin, Nil
Llinàs del Torrent, Clàudia
Argerich, Josep
Gómez Acero, Laura
Sahlholm, Kristoffer
Ferré, Sergi
Pardo, Leonardo
Ciruela Alférez, Francisco
author_role author
author2 Casajuana-Martin, Nil
Llinàs del Torrent, Clàudia
Argerich, Josep
Gómez Acero, Laura
Sahlholm, Kristoffer
Ferré, Sergi
Pardo, Leonardo
Ciruela Alférez, Francisco
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Adenosina
Dopamina
Antipsicòtics
Adenosine
Dopamine
Antipsychotic drugs
topic Adenosina
Dopamina
Antipsicòtics
Adenosine
Dopamine
Antipsychotic drugs
description The striatal dopamine D2 receptor (D2R) is generally accepted to be involved in positive symptoms of schizophrenia and is a main target for clinically used antipsychotics. D2R are highly expressed in the striatum, where they form heteromers with the adenosine A2A receptor (A2AR). Changes in the density of A2AR-D2R heteromers have been reported in postmortem tissue from patients with schizophrenia, but the degree to which A2R 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 A2AR-D2R heteromerization in mammalian cells using a NanoBiT assay. After 16 h of exposure, a significant increase in the density of A2AR-D2R 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 A2AR-D2R 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 D2R, inducing a clash with A2AR, while the extended binding mode of haloperidol and aripiprazole stabilizes a specific conformation of the second extracellular loop of D2R that enhances the interaction with A2AR. It is proposed that an increase in A2AR-D2R heteromerization is involved in the extrapyramidal side effects (EPS) of antipsychotics and that the specific clozapine-mediated destabilization of A2AR-D2R heteromerization can explain its low EPS liability.
publishDate 2023
dc.date.none.fl_str_mv 2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/198681
url https://hdl.handle.net/2445/198681
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1016/j.biopha.2023.114327
Biomedicine & Pharmacotherapy, 2023, vol. 160, p. 114327
https://doi.org/10.1016/j.biopha.2023.114327
dc.rights.none.fl_str_mv cc by-nc-nd (c) Valle León, Marta et al., 2023
https://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by-nc-nd (c) Valle León, Marta et al., 2023
https://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier Masson SAS
publisher.none.fl_str_mv Elsevier Masson SAS
dc.source.none.fl_str_mv Articles publicats en revistes (Patologia i Terapèutica Experimental)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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