The mGlu5 Receptor Protomer-Mediated Dopamine D2 Receptor Trans-Inhibition Is Dependent on the Adenosine A2A Receptor Protomer: Implications for Parkinson’s Disease
Wilber Romero‐Fernandez, Jaume Taura, René A. J. Crans, Marc López‐Cano, Ramón Fores‐Pons, Manuel Narváez, Jens Carlsson, Francisco Ciruela, Kjell Fuxé, Dasiel O. Borroto‐Escuela
Abstract
Abstract 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.