Angiotensin II type 1/adenosine A2A 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 D-2 receptors (D(2)Rs). Striatal D2R functioning may be finely regulated by either adenosine A(2A) receptor (A(2A)R) or angiotensin receptor type 1 (AT(1)R) through putative receptor heteromers. Here, we examined whether A(2A)R and AT(1)R may oligomerize in the striatum to synergistically modulate dopaminergic transmission. First, by using bioluminescence resonance energy transfer, we demonstrated a physical AT(1)R-A(2A)R interaction in cultured cells. Interestingly, by protein-protein docking and molecular dynamics simulations, we described that a stable heterotetrameric interaction may exist between AT(1)R and A(2A)R bound to antagonists (i. e. losartan and istradefylline, respectively). Accordingly, we subsequently ascertained the existence of AT(1)R/A(2A)R 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 AT(1)R/A(2A)R 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 AT(1)R/A(2A)R oligomers with potential usefulness for the therapeutic management of TD.