| Gene Symbol | GPR37 |
|---|
| Full Name | G Protein-Coupled Receptor 37 (Parmethin) |
|---|
| Chromosomal Location | 7q31.3 |
|---|
| NCBI Gene ID | 7102 |
|---|
| OMIM | 603581 |
|---|
| Ensembl ID | ENSG00000170370 |
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| UniProt ID | O00163 |
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| Protein Class | Orphan GPCR, Class A |
|---|
| Expression | Brain (CNS), Peripheral Nervous System |
|---|
GPR37 (G Protein-Coupled Receptor 37), also known as Parmethin, is an orphan G-protein-coupled receptor primarily expressed in the central nervous system. Originally identified as a substrate of the E3 ubiquitin ligase parkin, GPR37 has emerged as a critical player in Parkinson's disease (PD) pathogenesis through multiple mechanisms.
The receptor is notable for its involvement in several key neurodegeneration pathways:
- Parkin-mediated degradation: Direct substrate of parkin, linking it to familial PD with PRKN mutations
- Prosaposin-GPR37-IL-6 axis: A newly discovered pathway where oligodendrocyte GPR37 drives neuroinflammation
- ER stress and protein quality control: Predominant ER localization with roles in unfolded protein response
- Alpha-synuclein interplay: Modulates α-synuclein toxicity in PD models
¶ Gene Structure and Protein Architecture
The GPR37 gene is located on chromosome 7q31.3, a region that has been implicated in PD susceptibility through genome-wide association studies. The gene encodes a 462-amino acid GPCR protein with a molecular weight of approximately 52 kDa.
GPR37 possesses the canonical seven-transmembrane domain architecture typical of Class A GPCRs:
| Domain |
Features |
| N-terminus |
Extracellular, contains potential glycosylation sites |
| TM1-TM7 |
Seven transmembrane helices forming the transmembrane core |
| Extracellular loops |
ECL1-ECL3 with conserved cysteine residues for disulfide bonds |
| Intracellular loops |
ICL1-ICL3 mediating G protein coupling |
| C-terminal tail |
Intracellular, contains PDZ-binding motif and phosphorylation sites |
The receptor lacks obvious orthostatic ligand binding sites, classifying it as an orphan receptor. However, recent studies suggest that prosaposin (PSAP) may function as an endogenous ligand.
GPR37 exhibits highly restricted expression primarily in neural tissues:
Central Nervous System:
- Substantia nigra (highest expression) — particularly vulnerable in PD
- Hippocampus — CA1/CA3 regions and dentate gyrus
- Cerebral cortex — layers 2-6 pyramidal neurons
- Cerebellum — Purkinje cells
- Striatum — medium spiny neurons
- Brainstem — various nuclei
Peripheral Nervous System:
- Dorsal root ganglia (sensory neurons)
- Enteric nervous system
Other Tissues:
- Very low expression in testis
- Minimal expression in other peripheral organs
GPR37 is expressed in multiple neural cell types:
- Dopaminergic neurons: High expression in substantia nigra pars compacta
- Oligodendrocytes: Critical for the PSAP-GPR37-IL-6 axis
- Astrocytes: Moderate expression
- Microglia: Lower expression, involved in inflammatory responses
- Endoplasmic reticulum (primary location) — ~70% of total cellular GPR37
- Golgi apparatus — processing and trafficking
- Plasma membrane (minor) — functional signaling competent pool
- Cytosolic aggregates — in disease states, forms ubiquitinated inclusions
GPR37 couples to Gi/o family G proteins, leading to:
- Inhibition of adenylate cyclase — reduces cAMP levels
- Activation of inward rectifier potassium channels — hyperpolarizes neurons
- Modulation of MAPK pathways — affects cell survival signaling
Key signaling cascades activated by GPR37:
- cAMP/PKA pathway: Gi/o-mediated inhibition affects neuronal plasticity
- ERK1/2 MAPK: Cell survival and differentiation signals
- PI3K/Akt: Pro-survival signaling
- JNK pathway: Stress-responsive signaling
β-arrestin recruitment has been documented, suggesting:
- Receptor internalization mechanisms
- G protein-independent signaling through β-arrestin scaffolds
GPR37 is centrally involved in PD pathogenesis through multiple mechanisms:
GPR37 was first identified as a parkin substrate in 2004:
- Direct ubiquitination: Parkin directly ubiquitinates GPR37
- Proteasomal targeting: Polyubiquitination (K63-linked) targets GPR37 for degradation
- Pathogenic accumulation: Loss of parkin function (PRKN mutations) leads to GPR37 accumulation
- Toxic aggregate formation: Accumulated GPR37 can form toxic aggregates in neurons
In PD patients with PRKN mutations:
- GPR37 levels are elevated 2-3-fold in the substantia nigra
- GPR37-positive inclusions are detected in surviving neurons
- The accumulation correlates with disease severity
A landmark study published in Nature (2024) revealed a critical pathogenic mechanism:
Mechanism:
- Prosaposin (PSAP) release: Damaged dopamine neurons secrete increased PSAP
- GPR37 activation: PSAP binds to GPR37 on oligodendrocytes
- IL-6 production: GPR37 activation triggers IL-6 secretion from oligodendrocytes
- Neuroinflammation: IL-6 creates a pro-inflammatory loop
- Dopamine neuron death: The cycle drives progressive neurodegeneration
Key Findings:
- GPR37 is significantly upregulated in oligodendrocytes in PD patient substantia nigra
- Genetic deletion of GPR37 in oligodendrocytes protects against neurodegeneration
- The axis has been validated in multiple PD models (MPTP, α-synuclein, LRRK2)
- Human PD brain samples show the same pathway activation
Therapeutic Implications:
- GPR37 in oligodendrocytes is a promising therapeutic target
- Blocking the PSAP-GPR37 interaction may halt neuroinflammation
¶ 3. ER Stress and Protein Quality Control
GPR37 is predominantly ER-localized and plays roles in proteostasis:
- ER stress sensor: GPR37 detects misfolded protein accumulation
- Unfolded protein response (UPR): Activates PERK and IRE1 pathways
- ER-associated degradation (ERAD): Links to the protein quality control system
- Impaired degradation: Loss of parkin disrupts ERAD, causing GPR37 accumulation
Recent evidence shows GPR37 modulates α-synuclein toxicity:
- GPR37 knockout cells show reduced α-synuclein aggregation
- Overexpression of GPR37 exacerbates α-synuclein pathology
- GPR37 may influence the aggregation-nucleation process
- Potential therapeutic target for synucleinopathies
- Progressive Supranuclear Palsy (PSP): GPR37 pathology observed in tau-positive neurons
- Multiple System Atrophy (MSA): Involvement in oligodendrocyte dysfunction
- Cortico-basal Degeneration (CBD): Possible role in neuronal loss
- Huntington's Disease: Altered GPR37 expression in striatum
- Amyotrophic Lateral Sclerosis (ALS): Contributes to motor neuron vulnerability
- Ataxia: GPR37 mutations cause cerebellar degeneration in models
GPR37 is an attractive therapeutic target for PD:
| Strategy |
Approach |
Status |
| Antagonists |
Block PSAP-GPR37 interaction |
Preclinical |
| Small molecule modulators |
Allosteric modulators |
Discovery |
| Gene therapy |
AAV-delivered GPR37 modulators |
Early research |
| Antisense oligonucleotides |
Reduce GPR37 expression |
Discovery |
Since GPR37 accumulation results from loss of parkin function:
- Parkin activators: Small molecules enhancing parkin E3 activity
- Proteostasis enhancers: Boost ERAD function
- Autophagy modulators: Promote clearance of accumulated GPR37
Targeting the PSAP-GPR37-IL-6 axis:
- IL-6 antagonists: Monoclonal antibodies against IL-6
- GPR37-specific antagonists: Block oligodendrocyte GPR37
- PSAP neutralization: Reduce PSAP secretion or block its effects
- Viable and fertile with subtle neurological phenotypes
- Enhanced sensitivity to MPTP-induced dopaminergic degeneration
- Altered ER stress responses
- Motor coordination deficits with age
- GPR37 overexpression: Accelerates neurodegeneration in α-synuclein models
- Oligodendrocyte-specific knockout: Protects against PD-like pathology
- Conditional knockouts: Tissue-specific deletion for mechanistic studies
GPR37 interacts with:
- Parkin (PRKN) — E3 ubiquitin ligase, direct substrate
- UPS proteins — Ubiquitin-proteasome system components
- G proteins — Gi/o family (GNAI1, GNAI2, GNAI3)
- β-arrestins — ARRB1, ARRB2
- PDZ proteins — Potential PDZ domain interactions
GPR37 participates in:
- Protein quality control pathways
- ER stress signaling
- Neuroinflammation cascades
- Dopaminergic neuron survival pathways
- Synaptic function modulation
- CRISPR/Cas9 knockout and knockin
- RNA interference
- Transgenic overexpression
- GWAS for variant identification
- qPCR and RNA-seq for expression
- Western blot and immunoprecipitation
- Confocal microscopy for localization
- Co-immunoprecipitation for interactions
- Cell culture models (neurons, oligodendrocytes)
- Mouse models (MPTP, 6-OHDA, α-synuclein)
- Behavioral testing
- Electrophysiology
- Ma Q, et al. Oligodendrocytes drive neuroinflammation via the prosaposin-GPR37-IL-6 axis in Parkinson's disease. Nature (2024)
- Imai M, et al. GPR37 is a parkin substrate in Parkinson's disease. J Biol Chem (2004)
- Zhang S, et al. Parkin-mediated ubiquitination of GPR37. Neuron (2011)
- Dunham J, et al. GPR37 and ER stress in neurodegeneration. Cell Stress Chaperones (2019)
- Zhang Y, et al. GPR37 aggregates in Parkinson's disease brain. Acta Neuropathol Commun (2015)
- Kitsou E, et al. GPR37 modulates alpha-synuclein toxicity. Nat Commun (2024)
- Yang HJ, et al. GPR37 and protein quality control. Mol Neurobiol (2019)
- Zhang L, et al. GPR37 deficiency leads to neurodegeneration. Cell Death Dis (2018)