The ADORA1 mutation linked to early-onset Parkinson's disease alters adenosine A1-A2A receptor heteromer formation and function

Adenosine modulates neurotransmission through inhibitory adenosine A1 receptors (A1Rs) and stimulatory A2A receptors (A2ARs). These G protein-coupled receptors are involved in motor function and related to neurodegenerative diseases such as Parkinson's disease (PD). An autosomal-recessive m...

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Autores: Sarasola, Laura I., Llinàs del Torrent, Clàudia, Pérez Arévalo, Andrea, Argerich, Josep, Casajuana-Martin, Nil, Chevigné, Andy, Fernández Dueñas, Víctor, Ferré, Sergi, Pardo, Leonardo, Ciruela Alférez, Francisco
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/191257
Acesso em linha:https://hdl.handle.net/2445/191257
Access Level:acceso abierto
Palavra-chave:Adenosina
Malaltia de Parkinson
Proteïnes G
Adenosine
Parkinson&apos
s disease
G Proteins
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spelling The ADORA1 mutation linked to early-onset Parkinson's disease alters adenosine A1-A2A receptor heteromer formation and functionSarasola, Laura I.Llinàs del Torrent, Clàudia Pérez Arévalo, AndreaArgerich, JosepCasajuana-Martin, NilChevigné, AndyFernández Dueñas, VíctorFerré, SergiPardo, LeonardoCiruela Alférez, FranciscoAdenosinaMalaltia de ParkinsonProteïnes GAdenosineParkinson&aposs diseaseG ProteinsAdenosine modulates neurotransmission through inhibitory adenosine A1 receptors (A1Rs) and stimulatory A2A receptors (A2ARs). These G protein-coupled receptors are involved in motor function and related to neurodegenerative diseases such as Parkinson's disease (PD). An autosomal-recessive mutation (G2797.44S) within the transmembrane helix (TM) 7 of A1R (A1RG279S) has been associated with the development of early onset PD (EOPD). Here, we aimed at investigating the impact of this mutation on the structure and function of the A1R and the A1R-A2AR heteromer. Our results revealed that the G2797.44S mutation does not alter A1R expression, ligand binding, constitutive activity or coupling to transducer proteins (Gαi, Gαq, Gα12/13, Gαs, β-arrestin2 and GRK2) in transfected HEK-293 T cells. However, A1RG279S weakened the ability of A1R to heteromerize with A2AR, as shown in a NanoBiT assay, which led to the disappearance of the heteromerization-dependent negative allosteric modulation that A1R imposes on the constitutive activity and agonist-induced activation of the A2AR. Molecular dynamic simulations allowed to propose an indirect mechanism by which the G2797.44S mutation in TM 7 of A1R weakens the TM 5/6 interface of the A1R-A2AR heteromer. Therefore, it is demonstrated that a PD linked ADORA1 mutation is associated with dysfunction of adenosine receptor heteromerization. We postulate that a hyperglutamatergic state secondary to increased constitutive activity and sensitivity to adenosine of A2AR not forming heteromers with A1R could represent a main pathogenetic mechanism of the EOPD associated with the G2797.44S ADORA1 mutation.Elsevier Masson SAS2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/191257Articles 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.2022.113896Biomedicine & Pharmacotherapy, 2022, vol. 156https://doi.org/10.1016/j.biopha.2022.113896cc by-nc-nd (c) Sarasola, Laura I. et al., 2022https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1912572026-05-27T06:46:51Z
dc.title.none.fl_str_mv The ADORA1 mutation linked to early-onset Parkinson's disease alters adenosine A1-A2A receptor heteromer formation and function
title The ADORA1 mutation linked to early-onset Parkinson's disease alters adenosine A1-A2A receptor heteromer formation and function
spellingShingle The ADORA1 mutation linked to early-onset Parkinson's disease alters adenosine A1-A2A receptor heteromer formation and function
Sarasola, Laura I.
Adenosina
Malaltia de Parkinson
Proteïnes G
Adenosine
Parkinson&apos
s disease
G Proteins
title_short The ADORA1 mutation linked to early-onset Parkinson's disease alters adenosine A1-A2A receptor heteromer formation and function
title_full The ADORA1 mutation linked to early-onset Parkinson's disease alters adenosine A1-A2A receptor heteromer formation and function
title_fullStr The ADORA1 mutation linked to early-onset Parkinson's disease alters adenosine A1-A2A receptor heteromer formation and function
title_full_unstemmed The ADORA1 mutation linked to early-onset Parkinson's disease alters adenosine A1-A2A receptor heteromer formation and function
title_sort The ADORA1 mutation linked to early-onset Parkinson's disease alters adenosine A1-A2A receptor heteromer formation and function
dc.creator.none.fl_str_mv Sarasola, Laura I.
Llinàs del Torrent, Clàudia
Pérez Arévalo, Andrea
Argerich, Josep
Casajuana-Martin, Nil
Chevigné, Andy
Fernández Dueñas, Víctor
Ferré, Sergi
Pardo, Leonardo
Ciruela Alférez, Francisco
author Sarasola, Laura I.
author_facet Sarasola, Laura I.
Llinàs del Torrent, Clàudia
Pérez Arévalo, Andrea
Argerich, Josep
Casajuana-Martin, Nil
Chevigné, Andy
Fernández Dueñas, Víctor
Ferré, Sergi
Pardo, Leonardo
Ciruela Alférez, Francisco
author_role author
author2 Llinàs del Torrent, Clàudia
Pérez Arévalo, Andrea
Argerich, Josep
Casajuana-Martin, Nil
Chevigné, Andy
Fernández Dueñas, Víctor
Ferré, Sergi
Pardo, Leonardo
Ciruela Alférez, Francisco
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Adenosina
Malaltia de Parkinson
Proteïnes G
Adenosine
Parkinson&apos
s disease
G Proteins
topic Adenosina
Malaltia de Parkinson
Proteïnes G
Adenosine
Parkinson&apos
s disease
G Proteins
description Adenosine modulates neurotransmission through inhibitory adenosine A1 receptors (A1Rs) and stimulatory A2A receptors (A2ARs). These G protein-coupled receptors are involved in motor function and related to neurodegenerative diseases such as Parkinson's disease (PD). An autosomal-recessive mutation (G2797.44S) within the transmembrane helix (TM) 7 of A1R (A1RG279S) has been associated with the development of early onset PD (EOPD). Here, we aimed at investigating the impact of this mutation on the structure and function of the A1R and the A1R-A2AR heteromer. Our results revealed that the G2797.44S mutation does not alter A1R expression, ligand binding, constitutive activity or coupling to transducer proteins (Gαi, Gαq, Gα12/13, Gαs, β-arrestin2 and GRK2) in transfected HEK-293 T cells. However, A1RG279S weakened the ability of A1R to heteromerize with A2AR, as shown in a NanoBiT assay, which led to the disappearance of the heteromerization-dependent negative allosteric modulation that A1R imposes on the constitutive activity and agonist-induced activation of the A2AR. Molecular dynamic simulations allowed to propose an indirect mechanism by which the G2797.44S mutation in TM 7 of A1R weakens the TM 5/6 interface of the A1R-A2AR heteromer. Therefore, it is demonstrated that a PD linked ADORA1 mutation is associated with dysfunction of adenosine receptor heteromerization. We postulate that a hyperglutamatergic state secondary to increased constitutive activity and sensitivity to adenosine of A2AR not forming heteromers with A1R could represent a main pathogenetic mechanism of the EOPD associated with the G2797.44S ADORA1 mutation.
publishDate 2022
dc.date.none.fl_str_mv 2022
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/2445/191257
url https://hdl.handle.net/2445/191257
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.2022.113896
Biomedicine & Pharmacotherapy, 2022, vol. 156
https://doi.org/10.1016/j.biopha.2022.113896
dc.rights.none.fl_str_mv cc by-nc-nd (c) Sarasola, Laura I. et al., 2022
https://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by-nc-nd (c) Sarasola, Laura I. et al., 2022
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 15.301629

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