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679437.pdf (2.26 MB)

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2017-05-12

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cc-by (c) Oliveira, Paulo A. et al., 2017
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/121970

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

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Recurs relacionat

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

Resum

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.

Matèries

Trastorns motors, Adenosina, Dopamina, Antipsicòtics, Neurotransmissors

Matèries (anglès)

Movement disorders, Adenosine, Dopamine, Antipsychotic drugs, Neurotransmitters

Citació

Col·leccions

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

Citació

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: 13 of August of 2026]. Available at: https://hdl.handle.net/2445/121970

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