GPR37 is an orphan G protein-coupled receptor (GPCR) expressed in brain regions such as cerebellum, corpus callosum, caudate nucleus, putamen, hippocampus and substantia nigra. The physiological function of this receptor has yet to be elucidated. A recent study has shown that GPR37 mediates the control of oligodendrocyte differentiation, but there is little information on the role of GPR37 in other glial cells and neurons. GPR37 is also known as a parkin-associated endothelin-receptor-like receptor (Pael receptor) as it was originally identified as a substrate of parkin, an E3 ubiquitin ligase encoded by the PARK2 gene involved in ubiquitination and proteasome-mediated degradation/clearance of misfolded proteins. Mutations in the PARK2 gene that lead to the loss of the ubiquitin ligase activity of parkin are the most common cause of autosomal recessive juvenile parkinsonism. Consistently, an insoluble form of GPR37 has been reported to accumulate in the brains of AR-JP patients, suggesting a neuropathological role of this receptor in PD. In line with this, mice lacking GPR37 are partially protected against dopaminergic cell death caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Nevertheless, in heterologous expression systems, GPR37 matures and is exported from the endoplasmic reticulum to the cell surface, where its long extracellular N-terminus is rapidly and constitutively cleaved by metalloproteinases (MPs). Thus, the GPR37 ectodomain (i.e., ecto-GPR37) is released from cells by shedding, a phenomenon rarely described for GPCRs. Importantly, MPs have received much attention since they can cleave many protein substrates (i.e., α-synuclein, amyloid precursor protein, and Apolipoprotein E receptor), thus playing a potential role in neurodegenerative diseases. Indeed, altered levels of MPs have been described in post-mortem brain samples from PD and AD subjects.
While setting out to derophanize GPR37, we are also exploiting the potential biomarker possibilities of ecto-GPR37 in PD. Importantly, this project is funded by The Michael J. Fox Foundation for Parkinson’s Research (MJFF), Grant ID: MJFF-001051.
Additional reading:
Ecto-GPR37: a potential biomarker for Parkinson's disease. (2021) Morató, X., García-Esparcia, P., Argerich, J., Llorens, F., Zerr, I., Paslawski, W., Borràs, E., Sabidó, E., Petäjä-Repo, U.E., Fernández-Dueñas, V., Ferrer, I., Svenningsson, P. & Ciruela, F. Translational Neurodegeneration 10, 8..
G protein-coupled receptor 37 (GPR37) emerges as an important modulator of adenosinergic transmission in the striatum. (2019) Morató, X., Cunha, R.A. & Ciruela, F. . Neural Regeneration Research 14 (11), 1912-1914.
Chronic adenosine A2A receptor blockade induces locomotor sensitization and potentiates striatal LTD IN GPR37-deficient mice. (2019) Morató, X., Gonçalves, F.Q., Lopes, J.P., Jauregui, O., Soler, C., Fernández-Dueñas, V., Cunha, R.A. & Ciruela, F. Journal of Neurochemistry 148 (6), 796-809.