The mGlu(5) Receptor Protomer-Mediated Dopamine D(2) Receptor Trans-Inhibition Is Dependent on the Adenosine A(2A) Receptor Protomer: Implications for Parkinson’s Disease

The adenosine A(2A) receptor (A(2A)R), dopamine D(2) receptor (D(2)R) and metabotropic glutamate receptor type 5 (mGluR(5)) form A(2A)R-D(2)R-mGluR(5) heteroreceptor complexes in living cells and in rat striatal neurons. In the current study, we present experimental data supporting the view that the A(2A)R protomer plays a major role in the inhibitory modulation of the density and the allosteric receptor-receptor interaction within the D(2)R-mGluR(5) heteromeric component of the A(2A)R-D(2)R-mGluR(5) complex in vitro and in vivo. The A(2A)R and mGluR(5) protomers interact and modulate D(2)R protomer recognition and signalling upon forming a trimeric complex from these receptors. Expression of A(2A)R in HEK293T cells co-expressing D(2)R and mGluR(5) resulted in a significant and marked increase in the formation of the D(2)R-mGluR(5) heteromeric component in both bioluminescence resonance energy transfer and proximity ligation assays. A highly significant increase of the the high-affinity component of D(2)R (D2R(Ki High)) values was found upon cotreatment with the mGluR(5) and A(2A)R agonists in the cells expressing A(2A)R, D(2)R and mGluR(5) with a significant effect observed also with the mGluR(5) agonist alone compared to cells expressing only D(2)R and mGluR(5). In cells co-expressing A(2A)R, D(2)R and mGluR(5), stimulation of the cells with an mGluR(5) agonist like or D(2)R antagonist fully counteracted the D(2)R agonist-induced inhibition of the cAMP levels which was not true in cells only expressing mGluR(5) and D(2)R. In agreement, the mGluR(5)-negative allosteric modulator raseglurant significantly reduced the haloperidol-induced catalepsy in mice, and in A(2A)R knockout mice, the haloperidol action had almost disappeared, supporting a functional role for mGluR(5) and A(2A)R in enhancing D(2)R blockade resulting in catalepsy. The results represent a relevant example of integrative activity within higher-order heteroreceptor complexes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12035-022-02946-9.