Angiotensin II type 1/adenosine A _2A receptor oligomers: a novel target for tardive dyskinesia

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 A_2A receptor (A_2AR) or angiotensin receptor type 1 (AT₁R) through putative receptor heteromers. Here, we examined whether A_2AR and AT₁R may oligomerize in the striatum to synergistically modulate dopaminergic transmission. First, by using bioluminescence resonance energy transfer, we demonstrated a physical AT₁R-A_2AR 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 A_2AR bound to antagonists (i.e. losartan and istradefylline, respectively). Accordingly, we subsequently ascertained the existence of AT₁R/A_2AR 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/A_2AR 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/A_2AR oligomers with potential usefulness for the therapeutic management of TD.