GPR37 and GPR37L1 differently interact with dopamine 2 receptors in live cells

Abstract

Receptor-receptor interactions are essential to fine tune receptor responses and new techniques enable closer characterization of the interactions between involved proteins directly in the plasma membrane. Fluorescence cross-correlation spectroscopy (FCCS), which analyses concurrent movement of bound molecules with single-molecule detection limit, was here used to, in live N2a cells, study interactions between the Parkinson's disease (PD) associated orphan receptor GPR37, its homologue GPR37L1, and the two splice variants of the dopamine 2 receptor (D2R). An interaction between GPR37 and both splice forms of D2R was detected. 4-phenylbutyrate (4-PBA), a neuroprotective chemical chaperone known to increase GPR37 expression at the cell surface, increased the fraction of interacting molecules. The interaction was also increased by pramipexole, a D2R agonist commonly used in the treatment of PD, indicating a possible clinically relevance. Cross-correlation, indicating interaction between GPR37L1 and the short isoform of D2R, was also detected. However, this interaction was not changed with 4-PBA or pramipexole treatment. Overall, these data provide further evidence that heteromeric GPR37-D2R exist and can be pharmacologically modulated, which is relevant for the treatment of PD. This article is part of the Special Issue entitled ‘Receptor heteromers and their allosteric receptor-receptor interactions’.

Ecto-GPR37: a potential biomarker for Parkinson’s disease

“…Although GPR37 has been postulated to be the receptor for the neuroprotective and glioprotective factors prosaptide and prosaposin [37,38], the precise physiological function of the receptor remains elusive. Recent studies have reported some alternative functions of GPR37, such as the chaperone-like activity that controls the cell surface targeting and function of adenosine and dopamine receptors [18,39], and participation in the Wnt coreceptor LRP6 maturation [40]. Remarkably, it has been demonstrated that the GPR37 N-terminus is processed by MPs, leading to the generation of different GPR37 N- Fig.…”

Deletion of Orphan G Protein-Coupled Receptor GPR37L1 in Mice Alters Cardiovascular Homeostasis in a Sex-Specific Manner

“…Furthermore, electrophysiology in hippocampal slice culture also revealed that D-aspartate induced currents in astrocytes were comparable between wildtype and Gpr37l1 global knockout mice, and kainite- and AMPA-induced currents in C1 pyramidal neurons were also the same between genotypes ( Jolly et al, 2018 ), suggesting that loss of GPR37L1 does not affect neuronal glutamate signaling at least in the hippocampal region of Gpr37l1 knockout mice. Alternatively, it has been suggested that GPR37L1 associates with the dopamine D 2 receptor (D 2 ) in cells, as analyzed by fluorescence cross-correlation spectroscopy ( Hertz et al, 2018 ), though a negative control was not used in these experiments, and a direct interaction between GPR37L1 and the D 2 receptor has not been shown.…”

GPR37 is processed in the N‐terminal ectodomain by ADAM10 and furin

“…The G protein-coupled receptor 37 (GPR37) is a class A (rhodopsin-type) G protein-coupled receptor (GPCR) that is highly expressed in several brain regions. 1 It is involved in dopaminergic and adenosinergic signaling pathways, [2][3][4][5][6] and consequently has been implicated in the pathophysiology of Parkinson's disease 7,8 along with certain other brain pathologies. 9,10 The receptor is also found in astrocytes, 11 and especially in oligodendrocytes, 12,13 with a demonstrated role in their differentiation and myelination.…”