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

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.

Distinct Dopamine D2 Receptor Antagonists Differentially Impact D2 Receptor Oligomerization

“…In addition, our D 2 R homodimer model with a TM5–TM6–TM5–TM6 interface, in accordance with a previously published D 2 R–mGlu5 heterodimer model presented by Qian et al (2018) [40], is physically stable over microsecond-length MD simulations. In addition to this homodimeric interface, it has been widely described that D 2 R heteromerizes through a TM4–TM5–TM4–TM5 interface with other class A GPCRs, such as A 2a and AT1 receptors [35,36,37,38,39]. Therefore, our results raise questions about the oligomerization interfaces D 2 R may form.…”

“…On the other hand, successive deletion of TM domains of the D 2 R and cysteine cross-linking studies revealed that the most critical areas involved in the intermolecular hydrophobic interactions for dimerization resided in TM4 [33,34]. In addition, the TM4–TM5–TM4–TM5 and TM5–TM6–TM5–TM6 interfaces have been widely described to be involved in D 2 R hetero-oligomerization with other class A GPCRs [35,36,37,38,39,40]. In 2014, Guitart et al [41] reported that dopamine D 1 receptor (D 1 R) TM5- or TM6-derived single peptides were able to reduce D 1 R homodimerization.…”

Biased Activation Mechanism Induced by GPCR Heterodimerization: Observations from μOR/δOR Dimers

“…MODELLER V9.21 was used to rebuild the missing residues in ICL3 of δOR (residue number: 245–250), H8 of μOR (residue number: 346–352), and H8 of δOR (residue number: 329–335), as done in many computational works of GPCRs. − Following a general construction way of GPCR dimers in the absence of corresponding crystal structures, ,, the two monomers (μOR and δOR) were aligned onto the μOR homodimer crystal structure (PDB ID: 5C1M) with the TM1-TM2-H8/TM1-TM2-H8 interface, which was taken as the input of ROSETTA to further refine its configuration. Similar to docking operations of Rosetta in some MD works, , default values of some key parameters, for example, a perturbation of 3 Å between proteins, 8° of tilt and 360° rotation around protein centers, were used to generate 1000 solutions. The best docked heterodimer was identified in terms of the ROSETTA interface score (I_sc) and acceptable membrane-compatibility, which was used to conduct subsequent MD simulation.…”

Advances in the allostery of angiotensin II type 1 receptor

“…Similarly, in the striatum, the combined use of two receptor antagonists inhibited the effects produced by the heterodimerization of adenosine A2A receptor (A2AR) and AT1R. These findings can be helpful for the treatment of tardive dyskinesia (TD) [ 91 ]. However, AT1R antagonist losartan enhanced the interaction between AT1R and dopamine D1 receptor (D1R).…”