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2017-05-12

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cc-by (c) Oliveira, Paulo A. et al., 2017
Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/121970

Angiotensin II type 1/adenosine A2A receptor oligomers: a novel target for tardive dyskinesia

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https://doi.org/10.1038/s41598-017-02037-z

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.

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Trastorns motors, Adenosina, Dopamina, Antipsicòtics, Neurotransmissors

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Movement disorders, Adenosine, Dopamine, Antipsychotic drugs, Neurotransmitters

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Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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OLIVEIRA, Paulo A., et al. Angiotensin II type 1/adenosine A2A receptor oligomers: a novel target for tardive dyskinesia. Scientific Reports. 2017. Vol. 7, num. 1857. ISSN 2045-2322. [consulted: 17 of August of 2026]. Available at: https://hdl.handle.net/2445/121970

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