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

Scientific Reports
Paulo A de OliveiraFrancisco Ciruela

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 an...Continue Reading

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Citations

Apr 17, 2019·International Journal of Molecular Sciences·Elise WoutersChristophe Stove
May 11, 2021·Frontiers in Synaptic Neuroscience·Tamara KobiecSantiago Pérez-Lloret

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Methods Mentioned

BETA
confocal microscopy
BRET
transfection
Assay

Software Mentioned

ROSETTA
ROSIE
AMBER14SB
VMD
CHIMERA
Autodock4
LISA
ROSIE webserver
Image J
MODELLER

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