| GPR37 Protein | |
|---|---|
| Protein Name | GPR37 (Parmethin) |
| Gene Symbol | [GPR37](/genes/gpr37) |
| UniProt ID | [O00163](https://www.uniprot.org/uniprot/O00163) |
| Molecular Weight | ~70 kDa (predicted from sequence) |
| Subcellular Localization | Endoplasmic reticulum, Plasma membrane |
| Protein Family | GPCR Class A (Orphan, D6 subfamily) |
| Ligand | Orphan (no confirmed endogenous ligand) |
GPR37 (G protein-coupled receptor 37), also known as Parmethin, is an orphan G-protein-coupled receptor primarily expressed in the central nervous system[1]. GPR37 is a well-characterized substrate of the E3 ubiquitin ligase parkin, and its accumulation in parkin-deficient conditions has been directly implicated in Parkinson's Disease pathogenesis[2]. GPR37 also shows pathology in other tauopathies including Progressive Supranuclear Palsy (PSP) and is being investigated as a potential biomarker and therapeutic target[3].
The GPR37 gene is located on chromosome 7q31 and encodes a 613-amino acid protein. The gene is highly expressed in brain, particularly in dopaminergic neurons of the substantia nigra pars compacta, cerebellar Purkinje cells, and pyramidal neurons of the hippocampus and cortex. Alternative splicing generates multiple transcript variants, though the full functional significance of isoform diversity remains under investigation.
GPR37 adopts the canonical seven-transmembrane (7TM) alpha-helical fold of Class A GPCRs[2:1]:
The lack of a confirmed endogenous ligand classifies GPR37 as an orphan receptor. However, structural studies suggest it may be capable of ligand binding if an appropriate agonist is identified.
GPR37 is a paradigmatic substrate of parkin, the E3 ubiquitin ligase mutated in autosomal recessive juvenile-onset Parkinson's disease[1:1]:
Despite its characterization as an orphan receptor, GPR37 appears to signal through Gi/o-type G proteins[2:2]:
GPR37 is predominantly localized to the endoplasmic reticulum in many cell types[2:3]:
| Partner | Interaction Type | Functional Consequence |
|---|---|---|
| Parkin | E3 ligase substrate | Monoubiquitination, trafficking regulation |
| GPR37L1 | Heterodimerization | May modulate ligand binding and signaling |
| Necdin | Protein interaction | Neuronal survival regulation |
| CDCrel-1 | Co-purification | Possible role in dopamine release |
| PAWR/PRKC | Protein interaction | Apoptosis regulation pathway |
GPR37 dysfunction is strongly linked to PD pathogenesis[1:2]:
Parkin Deficiency and GPR37 Accumulation: In the absence of functional parkin (loss-of-function mutations cause autosomal recessive juvenile PD), GPR37 accumulates in neurons:
Pathogenic Mechanisms:
Lewy Body Pathology: GPR37 has been detected in Lewy bodies in PD substantia nigra neurons, suggesting it is part of the pathologic inclusions that define this disease.
Therapeutic Implications: Enhancing parkin activity, promoting GPR37 clearance, or developing GPR37 agonists are all being explored as PD therapeutic strategies[3:1].
GPR37 immunoreactivity is observed in other neurodegenerative conditions beyond PD[4]:
Progressive Supranuclear Palsy (PSP): GPR37-positive inclusions are found in PSP brains, colocalizing with tau pathology. This suggests GPR37 dysfunction may be part of broader proteostasis failure in tauopathies.
Multiple System Atrophy (MSA): Some GPR37 pathology reported, though less prominent than in PD/PSP.
Huntington's Disease: Altered GPR37 expression patterns observed in HD models, suggesting involvement in multiple neurodegenerative conditions.
GPR37L1 is the closest relative of GPR37 and shares similar structural features. GPR37L1 is primarily expressed in the brain and has been linked to:
GPR37 and GPR37L1 can form heterodimers, potentially modulating each other's function.
GPR37 is being investigated as a Parkinson's disease biomarker[3:2]:
Cerebrospinal Fluid (CSF) GPR37: Studies have detected GPR37 in CSF, with levels potentially altered in PD patients compared to controls. CSF GPR37 could serve as:
Technical considerations: Reliable quantification of GPR37 in CSF requires validated immunoassays; standardization across studies is needed.
Given GPR37's apparent Gi/o signaling and neuroprotective effects:
Rather than targeting GPR37 directly:
Imai Y, et al. An unfolded transmembrane protein GPR37 as a substrate of parkin. Journal of Biological Chemistry. 2004. ↩︎ ↩︎ ↩︎
Mandrik N, et al. GPR37 and GPR37L1 in neurodegeneration and neuroinflammation. Frontiers in Cellular Neuroscience. 2022. ↩︎ ↩︎ ↩︎ ↩︎
Yang J, et al. GPR37 in Parkinson's disease: pathology and therapeutic potential. npj Parkinson's Disease. 2023. ↩︎ ↩︎ ↩︎
Marui W, et al. GPR37 immunoreactivity in tauopathies. Brain Research. 2009. ↩︎