The role of parkinson's disease‐associated receptor GPR37 in the hippocampus: functional interplay with the adenosinergic system

Abstract

GPR37 is an orphan G protein-coupled receptor mostly enriched in brain areas such as the cerebellum, striatum, and hippocampus. Identified as a substrate of parkin, GPR37 has been suggested to play a role in Parkinson's disease. Distributed throughout the brain, the function of GPR37, however, remains unknown. We now provide the first mapping of GPR37 within the hippocampus, where GPR37 is widely expressed and localized at the level of the extrasynaptic plasma membrane of dendritic spines, dendritic shafts, and axon terminals. GPR37 per se does not appear to play a role in learning and memory, since knocking out GPR37 (GPR37-KO) did not alter the performance in different hippocampalrelated memory tasks. This is in agreement with slice electrophysiology experiments showing no differences both in short-term plasticity paired-pulse facilitation and long-term potentiation between WT and GPR37-KO mice. However, we report a potential functional interaction between GPR37 and adenosine A 2A receptors (A 2A R) in the hippocampus, with A 2A R modulating the GPR37-associated phenotype. Thus, the absence of GPR37 appeared to sensitize mice to hippocampal A 2A R-mediated signaling, as observed by the effect of the A 2A R antagonist SCH58261 increasing synaptic depotentiation, reducing novel object recognition memory and reverting the anxiolytic effect of GPR37 deletion. Collectively, these findings afford insight into the localization and role of the orphan GPR37 within the hippocampus with potential involvement in A 2A R function (i.e., A 2A R sensitization).

The Parkinson's-disease-associated receptor GPR37 undergoes metalloproteinase-mediated N-terminal cleavage and ectodomain shedding

“…It also remains to be investigated whether the shed ectodomain has any functional role. Neither can we fully exclude the possibility that the N-terminal processing has a role in a functional interplay of GPR37 with other receptors, a phenomenon that has been suggested to occur between GPR37 and adenosine A2A and dopamine D2 receptors (Gandía et al, 2015;Lopes et al, 2015), as well as the dopamine transporter (Marazziti et al, 2007). In addition, GPR37 has been recently identified in at least two screens for novel interacting partners for GPCRs, one identifying partners for the β 2 adrenergic receptor (Kittanakom et al, 2014) and the other for the glucagon-like peptide 1 receptor (Huang et al, 2013).…”

Chronic adenosine A2A receptor blockade induces locomotor sensitization and potentiates striatal LTD IN GPR37‐deficient mice

“…Overall, these results suggest that GPR37 deletion reduced anxiety‐like behavior, as previously reported (Lopes et al . ).…”

“…PVDF membranes were blocked with 5% (wt/vol) dry non‐fat milk in phosphate‐buffered saline (PBS, 137 mM NaCl, 2.7 mM KCl, 8 mM Na 2 HPO 4 , 2 mM KH 2 PO4, pH 7.4) containing 0.05% Tween‐20 (PBS‐T) during 2 h and immunoblotted using rabbit anti‐GPR37‐N (1 μg/mL) (Lopes et al . ), goat polyclonal anti‐A 2A R (Ref: sc‐7504, R‐18, 1 μg/mL; Santa Cruz Biotechnology Inc., Dallas, TX, USA,), and rabbit anti‐α‐actinin (RRID‐AB2223809, sc‐15335; 0.5 μg/mL; Santa Cruz Biotechnology Inc., Dallas, TX, USA) antibodies in blocking solution overnight at 4°C. PVDF membranes were washed with PBS‐T three times (5 min each) before incubation with either a horseradish peroxidase‐conjugated goat anti‐rabbit IgG (Ref: 65‐6120; 1/50 000; Pierce Biotechnology) or horseradish peroxidase‐conjugated rabbit anti‐goat IgG (Ref: 61‐1620; 1/20 000; Pierce Biotechnology) in blocking solution at 20°C during 2 h. After washing the PVDF membranes with PBS‐T three times (5 min each), the immunoreactive bands were developed using a chemiluminescent detection kit (Ref: 32109, Thermo Fisher Scientific, Waltham, MA, USA) and detected with an Amersham Imager 600 (Ref: 29083461, GE Healthcare Europe GmbH, Barcelona, Spain).…”

How does adenosine control neuronal dysfunction and neurodegeneration?

“…), and GPR37 (Lopes et al . ), as well as with enzymes such as adenosine deaminase (Gracia et al . ) or ecto‐5’‐nucleotidase (Augusto et al .…”