The Parkinson's disease-associated GPR37 receptor interacts with striatal adenosine A_2A receptor controlling its cell...

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_2AR) cell surface expression and function in vivo. In addition, we showed that GPR37 and A_2AR do oligomerize in the striatum. Thus, a close proximity of GPR37 and A_2AR 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_2AR cell surface expression that correlated well with an increased A_2AR agonist-mediated cAMP accumulation, both in primary striatal neurons and nerve terminals. Furthermore, GPR37-/- mice showed enhanced A_2AR agonist-induced catalepsy and an increased response to A_2AR antagonist-mediated locomotor activity. Overall, these results revealed a key role for GPR37 controlling A_2AR biology in the striatum, which may be relevant for PD management.