The Parkinson’s disease-associated GPR37 receptor interacts with striatal adenosine A(2A) receptor controlling its cell surface expression and function in vivo

G protein-coupled receptor 37 (GPR37) is an orphan receptor associated to Parkinson’s disease (PD) neuropathology. Here, we identified GPR37 as an inhibitor of adenosine A(2A) receptor (A(2A)R) cell surface expression and function in vivo. In addition, we showed that GPR37 and A(2A)R do oligomerize in the striatum. Thus, a close proximity of GPR37 and A(2A)R at the postsynaptic level of striatal synapses was observed by double-labelling post-embedding immunogold detection. Indeed, the direct receptor-receptor interaction was further substantiated by proximity ligation in situ assay. Interestingly, GPR37 deletion promoted striatal A(2A)R cell surface expression that correlated well with an increased A(2A)R agonist-mediated cAMP accumulation, both in primary striatal neurons and nerve terminals. Furthermore, GPR37−/− mice showed enhanced A(2A)R agonist-induced catalepsy and an increased response to A(2A)R antagonist-mediated locomotor activity. Overall, these results revealed a key role for GPR37 controlling A(2A)R biology in the striatum, which may be relevant for PD management.