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

Authors :
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
Source :
Scientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
Publication Year :
2017
Publisher :
Nature Portfolio, 2017.

Abstract

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.

Subjects

Subjects :
Medicine
Science

Details

Language :
English
ISSN :
20452322
Volume :
7
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Scientific Reports
Publication Type :
Academic Journal
Accession number :
edsdoj.627f7a95432f4193ae2fb95d8887e02b
Document Type :
article
Full Text :
https://doi.org/10.1038/s41598-017-02037-z