GPR37: The Orphan GPCR Linked to Parkinson's Disease and Neuroprotection
A comprehensive biomedical overview of GPR37 (Parkin-associated endothelin receptor-like receptor), covering its genomic architecture, expression patterns, disease associations, and functional implications in neurodegeneration.
Gene Information Card
| Symbol | GPR37 |
|---|---|
| Full Name | G protein-coupled receptor 37 |
| Gene Type | protein coding |
| Chromosomal Location | 7q31.33 |
| NCBI Gene ID | 2861 ncbi.nlm.nih.gov/gene/2861 |
| Ensembl ID | ENSG00000170835 |
| UniProt ID | O15354 |
| OMIM ID | 602583 |
| HGNC ID | 4494 |
| Aliases | Pael-R, ETBR-LP-1, hET(B)R-LP |
Description
GPR37 (G protein-coupled receptor 37), also known as Parkin-associated endothelin receptor-like receptor (Pael-R), is an orphan G-protein coupled receptor (GPCR) encoded by the GPR37 gene located on chromosome 7q31.33. It is a 7-pass transmembrane protein that shares sequence homology with endothelin receptors but does not bind endothelin ligands. GPR37 is predominantly expressed in the central nervous system, particularly in oligodendrocytes, neurons of the substantia nigra, and the cerebellum. It is a substrate of the E3 ubiquitin ligase Parkin (PARK2), and its accumulation due to Parkin dysfunction is a hallmark of autosomal recessive juvenile Parkinsonism (AR-JP). GPR37 is involved in various cellular processes, including protein folding, ER stress response, and dopamine neuron survival. It has also been implicated in the pathology of other neurodegenerative diseases, such as Alzheimer's disease and multiple sclerosis, and is being explored as a potential therapeutic target.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Parkinson's Disease (Autosomal Recessive Juvenile Parkinsonism) | GPR37 (Pael-R) is a substrate of Parkin. In the absence of functional Parkin, misfolded GPR37 accumulates in the endoplasmic reticulum (ER), triggering the unfolded protein response (UPR) and leading to ER stress-induced apoptosis of dopaminergic neurons in the substantia nigra. | Strong evidence from in vitro and in vivo models (e.g., Parkin knockout mice, cell culture studies) and human post-mortem brain tissue analysis. PMID: 11439183, 11517226. |
| Alzheimer's Disease | GPR37 expression is upregulated in reactive astrocytes in the brains of Alzheimer's disease patients. It may contribute to neuroinflammation and amyloid-beta pathology, though the exact mechanism is still under investigation. | Evidence from human post-mortem brain tissue analysis showing increased GPR37 immunoreactivity in glial cells. PMID: 23246005. |
| Multiple Sclerosis | GPR37 is expressed in oligodendrocytes and is involved in their differentiation and myelination. Dysregulation of GPR37 may contribute to impaired remyelination in MS lesions. | Evidence from studies on oligodendrocyte precursor cells (OPCs) and animal models of demyelination. PMID: 26965635. |
| Cancer (Potential) | GPR37 expression has been detected in various cancer cell lines and tissues, including glioblastoma and neuroblastoma. It may play a role in tumor cell proliferation and survival, but its oncogenic role is not fully characterized. | Evidence from cancer cell line databases (e.g., COSMIC, CCLE) and preliminary functional studies. PMID: 29059223. |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain (Cerebellum) | 11.2 | Medium |
| Brain (Substantia Nigra) | 9.8 | Medium |
| Brain (Cerebral Cortex) | 8.5 | Low |
| Spinal Cord | 6.1 | Low |
| Testis | 4.3 | Low |
| Adrenal Gland | 3.2 | Low |
| Other Tissues | <2.0 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (Neuroblastoma) | 15.4 | High expression; used as a model for neuronal function and Parkinson's disease studies. |
| U-87 MG (Glioblastoma) | 12.1 | High expression; potential role in tumor biology. |
| HEK293 (Embryonic Kidney) | 8.7 | Moderate expression; commonly used for recombinant protein expression and functional assays. |
| HeLa (Cervical Carcinoma) | 5.2 | Low expression. |
| HepG2 (Hepatocellular Carcinoma) | 2.1 | Very low expression. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1123C>T (p.Arg375Ter) | Nonsense | Rare | Predicted to result in a truncated, non-functional protein. Loss of function may contribute to GPR37 haploinsufficiency, though its direct pathological role in sporadic PD is unclear. |
| c.1558G>A (p.Val520Met) | Missense | Rare | Located in the C-terminal tail. May affect protein stability or interaction with Parkin, potentially leading to increased ER stress. |
| c.1369C>T (p.Pro457Ser) | Missense | Rare | Located in the 7th transmembrane domain. May alter receptor conformation and signaling, though functional studies are limited. |
| c.1048C>T (p.Arg350Cys) | Missense | Rare | Located in the 3rd intracellular loop. Could affect G-protein coupling or receptor trafficking. |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in GPR37, such as the nonsense mutation p.Arg375Ter, are predicted to result in a truncated protein that is likely degraded or non-functional. This could impair its normal role in neuronal survival and protein homeostasis, potentially increasing susceptibility to ER stress and neurodegeneration.
Gain of Function (GOF)
Gain-of-function mutations are not well-documented for GPR37. However, overexpression or accumulation of the wild-type protein, as seen in Parkin dysfunction, can be considered a toxic gain-of-function, leading to ER stress and cell death.
Dominant Negative (DN)
No dominant-negative mutations have been reported for GPR37. However, it is plausible that certain missense mutations could interfere with the function of the wild-type allele by forming non-functional heterodimers, though this remains speculative.
View complete mutation data：
Gene Ontology (GO)
| • G protein-coupled receptor activity | • protein binding |
| • signal transducer activity | • integral component of plasma membrane |
| • endoplasmic reticulum membrane | • cellular response to unfolded protein |
| • dopamine receptor signaling pathway | • nervous system development |
| • oligodendrocyte differentiation | • negative regulation of neuron apoptotic process |
Pathways
• Parkin-ubiquitin proteasome system (UPS) pathway
• Unfolded protein response (UPR) pathway
• G protein-coupled receptor signaling pathway
• Endothelin receptor signaling pathway (putative
• due to homology)
Protein Summary
GPR37 is a 613-amino acid, 7-transmembrane domain orphan GPCR. It is synthesized in the endoplasmic reticulum (ER) where it undergoes folding and quality control. In healthy cells, it is ubiquitinated by Parkin and targeted for proteasomal degradation. In Parkinson's disease, particularly in AR-JP, Parkin dysfunction leads to the accumulation of misfolded GPR37 in the ER, triggering the unfolded protein response (UPR) and ER stress-induced apoptosis. GPR37 is also involved in the regulation of dopamine neuron survival and oligodendrocyte differentiation. Its natural ligand remains unknown, but it may function as a receptor for prosaposin or other neuropeptides. The protein is cleaved into two subunits (N-terminal and C-terminal) that remain non-covalently associated. GPR37 has been shown to interact with other GPCRs, such as the dopamine D2 receptor, and may modulate their signaling.
Related Services
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| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| GPR37 Knockout HEK293 Cell Line | EDJ-KQ3861 | Human | 2861 | Details Get a Quote |
| GPR37L1 Knockout HEK293 Cell Line | EDJ-KQ6536 | Human | 9283 | Details Get a Quote |
| GPR37 Knockout HeLa Cell Line | EDJ-KQ26053 | Human | 2861 | Details Get a Quote |
| GPR37 Knockout HCT 116 Cell Line | EDJ-KQ24696 | Human | 2861 | Details Get a Quote |
| GPR37L1 Knockout HeLa Cell Line | EDJ-KQ55119 | Human | 9283 | Details Get a Quote |
| GPR37 Knockout A-549 Cell Line | EDJ-KQ61886 | Human | 2861 | Details Get a Quote |
| GPR37L1 Knockout A-549 Cell Line | EDJ-KQ63598 | Human | 9283 | Details Get a Quote |
| GPR37L1 Knockout HCT 116 Cell Line | EDJ-KQ72063 | Human | 9283 | Details Get a Quote |
