The mGlu Receptor Protomer-Mediated Dopamine D Receptor Trans-Inhibition Is Dependent on the Adenosine A Receptor Protomer: Implications for Parkinson's Disease.

The adenosine A receptor (AR), dopamine D receptor (DR) and metabotropic glutamate receptor type 5 (mGluR) form AR-DR-mGluR heteroreceptor complexes in living cells and in rat striatal neurons. In the current study, we present experimental data supporting the view that the AR protomer plays a major role in the inhibitory modulation of the density and the allosteric receptor-receptor interaction within the DR-mGluR heteromeric component of the AR-DR-mGluR complex in vitro and in vivo. The AR and mGluR protomers interact and modulate DR protomer recognition and signalling upon forming a trimeric complex from these receptors. Expression of AR in HEK293T cells co-expressing DR and mGluR resulted in a significant and marked increase in the formation of the DR-mGluR heteromeric component in both bioluminescence resonance energy transfer and proximity ligation assays. A highly significant increase of the the high-affinity component of DR (D2R values was found upon cotreatment with the mGluR and AR agonists in the cells expressing AR, DR and mGluR with a significant effect observed also with the mGluR agonist alone compared to cells expressing only DR and mGluR. In cells co-expressing AR, DR and mGluR, stimulation of the cells with an mGluR agonist like or DR antagonist fully counteracted the DR agonist-induced inhibition of the cAMP levels which was not true in cells only expressing mGluR and DR. In agreement, the mGluR-negative allosteric modulator raseglurant significantly reduced the haloperidol-induced catalepsy in mice, and in AR knockout mice, the haloperidol action had almost disappeared, supporting a functional role for mGluR and AR in enhancing DR blockade resulting in catalepsy. The results represent a relevant example of integrative activity within higher-order heteroreceptor complexes.