Angiotensin II type 1/adenosine A 2A receptor oligomers: a novel target for tardive dyskinesia

Abstract Tardive dyskinesia (TD) is a serious motor side effect that may appear after long-term treatment with neuroleptics and mostly mediated by dopamine D2 receptors (D2Rs). Striatal D2R functioning may be finely regulated by either adenosine A2A receptor (A2AR) or angiotensin receptor type 1 (AT...

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Autores principales:	Paulo A. de Oliveira, James A. R. Dalton, Marc López-Cano, Adrià Ricarte, Xavier Morató, Filipe C. Matheus, Andréia S. Cunha, Christa E. Müller, Reinaldo N. Takahashi, Víctor Fernández-Dueñas, Jesús Giraldo, Rui D. Prediger, Francisco Ciruela
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/627f7a95432f4193ae2fb95d8887e02b
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spelling	oai:doaj.org-article:627f7a95432f4193ae2fb95d8887e02b2021-12-02T11:52:19ZAngiotensin II type 1/adenosine A 2A receptor oligomers: a novel target for tardive dyskinesia10.1038/s41598-017-02037-z2045-2322https://doaj.org/article/627f7a95432f4193ae2fb95d8887e02b2017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02037-zhttps://doaj.org/toc/2045-2322Abstract Tardive dyskinesia (TD) is a serious motor side effect that may appear after long-term treatment with neuroleptics and mostly mediated by dopamine D2 receptors (D2Rs). Striatal D2R functioning may be finely regulated by either adenosine A2A receptor (A2AR) or angiotensin receptor type 1 (AT1R) through putative receptor heteromers. Here, we examined whether A2AR and AT1R may oligomerize in the striatum to synergistically modulate dopaminergic transmission. First, by using bioluminescence resonance energy transfer, we demonstrated a physical AT1R-A2AR interaction in cultured cells. Interestingly, by protein-protein docking and molecular dynamics simulations, we described that a stable heterotetrameric interaction may exist between AT1R and A2AR bound to antagonists (i.e. losartan and istradefylline, respectively). Accordingly, we subsequently ascertained the existence of AT1R/A2AR heteromers in the striatum by proximity ligation in situ assay. Finally, we took advantage of a TD animal model, namely the reserpine-induced vacuous chewing movement (VCM), to evaluate a novel multimodal pharmacological TD treatment approach based on targeting the AT1R/A2AR complex. Thus, reserpinized mice were co-treated with sub-effective losartan and istradefylline doses, which prompted a synergistic reduction in VCM. Overall, our results demonstrated the existence of striatal AT1R/A2AR oligomers with potential usefulness for the therapeutic management of TD.Paulo A. de OliveiraJames A. R. DaltonMarc López-CanoAdrià RicarteXavier MoratóFilipe C. MatheusAndréia S. CunhaChrista E. MüllerReinaldo N. TakahashiVíctor Fernández-DueñasJesús GiraldoRui D. PredigerFrancisco CiruelaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Paulo A. de Oliveira James A. R. Dalton Marc López-Cano Adrià Ricarte Xavier Morató Filipe C. Matheus Andréia S. Cunha Christa E. Müller Reinaldo N. Takahashi Víctor Fernández-Dueñas Jesús Giraldo Rui D. Prediger Francisco Ciruela Angiotensin II type 1/adenosine A 2A receptor oligomers: a novel target for tardive dyskinesia
description	Abstract Tardive dyskinesia (TD) is a serious motor side effect that may appear after long-term treatment with neuroleptics and mostly mediated by dopamine D2 receptors (D2Rs). Striatal D2R functioning may be finely regulated by either adenosine A2A receptor (A2AR) or angiotensin receptor type 1 (AT1R) through putative receptor heteromers. Here, we examined whether A2AR and AT1R may oligomerize in the striatum to synergistically modulate dopaminergic transmission. First, by using bioluminescence resonance energy transfer, we demonstrated a physical AT1R-A2AR interaction in cultured cells. Interestingly, by protein-protein docking and molecular dynamics simulations, we described that a stable heterotetrameric interaction may exist between AT1R and A2AR bound to antagonists (i.e. losartan and istradefylline, respectively). Accordingly, we subsequently ascertained the existence of AT1R/A2AR heteromers in the striatum by proximity ligation in situ assay. Finally, we took advantage of a TD animal model, namely the reserpine-induced vacuous chewing movement (VCM), to evaluate a novel multimodal pharmacological TD treatment approach based on targeting the AT1R/A2AR complex. Thus, reserpinized mice were co-treated with sub-effective losartan and istradefylline doses, which prompted a synergistic reduction in VCM. Overall, our results demonstrated the existence of striatal AT1R/A2AR oligomers with potential usefulness for the therapeutic management of TD.
format	article
author	Paulo A. de Oliveira James A. R. Dalton Marc López-Cano Adrià Ricarte Xavier Morató Filipe C. Matheus Andréia S. Cunha Christa E. Müller Reinaldo N. Takahashi Víctor Fernández-Dueñas Jesús Giraldo Rui D. Prediger Francisco Ciruela
author_facet	Paulo A. de Oliveira James A. R. Dalton Marc López-Cano Adrià Ricarte Xavier Morató Filipe C. Matheus Andréia S. Cunha Christa E. Müller Reinaldo N. Takahashi Víctor Fernández-Dueñas Jesús Giraldo Rui D. Prediger Francisco Ciruela
author_sort	Paulo A. de Oliveira
title	Angiotensin II type 1/adenosine A 2A receptor oligomers: a novel target for tardive dyskinesia
title_short	Angiotensin II type 1/adenosine A 2A receptor oligomers: a novel target for tardive dyskinesia
title_full	Angiotensin II type 1/adenosine A 2A receptor oligomers: a novel target for tardive dyskinesia
title_fullStr	Angiotensin II type 1/adenosine A 2A receptor oligomers: a novel target for tardive dyskinesia
title_full_unstemmed	Angiotensin II type 1/adenosine A 2A receptor oligomers: a novel target for tardive dyskinesia
title_sort	angiotensin ii type 1/adenosine a 2a receptor oligomers: a novel target for tardive dyskinesia
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/627f7a95432f4193ae2fb95d8887e02b
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Angiotensin II type 1/adenosine A 2A receptor oligomers: a novel target for tardive dyskinesia

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