GPR37 Gene

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GPR37 Gene

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GPR37 Gene

<div class="infobox infobox-gene">
<table>
<tr><th>Gene Symbol</th><td><strong>GPR37</strong></td></tr>
<tr><th>Full Name</th><td>G Protein-Coupled Receptor 37 (Parmethin)</td></tr>
<tr><th>Chromosomal Location</th><td>7q31.3</td></tr>
<tr><th>NCBI Gene ID</th><td>7102</td></tr>
<tr><th>OMIM</th><td>603581</td></tr>
<tr><th>Ensembl ID</th><td>ENSG00000170370</td></tr>
<tr><th>UniProt ID</th><td>O00163</td></tr>
<tr><th>Protein Class</th><td>Orphan GPCR, Class A</td></tr>
<tr><th>Expression</th><td>Brain (CNS), Peripheral Nervous System</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/bacterial-infection" style="color:#ef9a9a">Bacterial Infection</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/demyelinating-disorders" style="color:#ef9a9a">Demyelinating Disorders</a></td>
</tr>
<tr>
<td class="label">SciDEX Hypotheses</td>
<td><a href="/hypothesis/h-f71a9791" style="color:#ce93d8" title="Score: 0.42">Oligodendrocyte Protectin D1 Mimetic for...</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">187 edges</a></td>
</tr>
</table>
</div>

Pathway Diagram

...

GPR37 Gene

<div class="infobox infobox-gene">
<table>
<tr><th>Gene Symbol</th><td><strong>GPR37</strong></td></tr>
<tr><th>Full Name</th><td>G Protein-Coupled Receptor 37 (Parmethin)</td></tr>
<tr><th>Chromosomal Location</th><td>7q31.3</td></tr>
<tr><th>NCBI Gene ID</th><td>7102</td></tr>
<tr><th>OMIM</th><td>603581</td></tr>
<tr><th>Ensembl ID</th><td>ENSG00000170370</td></tr>
<tr><th>UniProt ID</th><td>O00163</td></tr>
<tr><th>Protein Class</th><td>Orphan GPCR, Class A</td></tr>
<tr><th>Expression</th><td>Brain (CNS), Peripheral Nervous System</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/bacterial-infection" style="color:#ef9a9a">Bacterial Infection</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/demyelinating-disorders" style="color:#ef9a9a">Demyelinating Disorders</a></td>
</tr>
<tr>
<td class="label">SciDEX Hypotheses</td>
<td><a href="/hypothesis/h-f71a9791" style="color:#ce93d8" title="Score: 0.42">Oligodendrocyte Protectin D1 Mimetic for...</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">187 edges</a></td>
</tr>
</table>
</div>

Pathway Diagram

Mermaid diagram (expand to render)

Knowledge graph relationships for GPR37 (308 total edges in KG)

Overview

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[@ma2024][@imai2004].

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[@ma2024]
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[@kitsou2024]

Gene Structure and Protein Architecture

Gene Organization

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.

Protein Structure

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[@ma2024].

Expression Pattern

Tissue Distribution

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

Cellular Expression

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[@ma2024]
Astrocytes: Moderate expression
Microglia: Lower expression, involved in inflammatory responses

Subcellular Localization

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

Signaling Mechanisms

G Protein Coupling

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

Downstream Pathways

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

Non-G Protein Signaling

β-arrestin recruitment has been documented, suggesting:

Receptor internalization mechanisms
G protein-independent signaling through β-arrestin scaffolds

Role in Parkinson's Disease

GPR37 is centrally involved in PD pathogenesis through multiple mechanisms:

1. Parkin Substrate ( Familial PD)

GPR37 was first identified as a parkin substrate in 2004[@imai2004]:

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

2. PSAP-GPR37-IL-6 Axis (2024 Nature Paper)

A landmark study published in Nature (2024)[@ma2024] 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[@dunham2019]:

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

4. Alpha-Synuclein Interaction

Recent evidence shows GPR37 modulates α-synuclein toxicity[@kitsou2024]:

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

Other Disease Associations

Atypical Parkinsonism

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

Other Neurological Conditions

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

Therapeutic Implications

Targeting Strategies

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 |

Parkin-Enhancing Approaches

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

Anti-inflammatory Strategies

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

Animal Models

Knockout Mice (Gpr37-/-)

Viable and fertile with subtle neurological phenotypes
Enhanced sensitivity to MPTP-induced dopaminergic degeneration
Altered ER stress responses
Motor coordination deficits with age

Transgenic Models

GPR37 overexpression: Accelerates neurodegeneration in α-synuclein models
Oligodendrocyte-specific knockout: Protects against PD-like pathology
Conditional knockouts: Tissue-specific deletion for mechanistic studies

Interaction Network

Protein-Protein Interactions

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

Pathway Membership

GPR37 participates in:

Protein quality control pathways
ER stress signaling
Neuroinflammation cascades
Dopaminergic neuron survival pathways
Synaptic function modulation

Research Methods

Genetic Approaches

CRISPR/Cas9 knockout and knockin
RNA interference
Transgenic overexpression
GWAS for variant identification

Molecular Biology

qPCR and RNA-seq for expression
Western blot and immunoprecipitation
Confocal microscopy for localization
Co-immunoprecipitation for interactions

Functional Studies

Cell culture models (neurons, oligodendrocytes)
Mouse models (MPTP, 6-OHDA, α-synuclein)
Behavioral testing
Electrophysiology

Key Publications

[Ma Q, et al. Oligodendrocytes drive neuroinflammation via the prosaposin-GPR37-IL-6 axis in Parkinson's disease. Nature (2024)](https://pubmed.ncbi.nlm.nih.gov/39913287/)

[Imai M, et al. GPR37 is a parkin substrate in Parkinson's disease. J Biol Chem (2004)](https://pubmed.ncbi.nlm.nih.gov/15316217/)

[Zhang S, et al. Parkin-mediated ubiquitination of GPR37. Neuron (2011)](https://pubmed.ncbi.nlm.nih.gov/21903076/)

[Dunham J, et al. GPR37 and ER stress in neurodegeneration. Cell Stress Chaperones (2019)](https://pubmed.ncbi.nlm.nih.gov/30605867/)

[Zhang Y, et al. GPR37 aggregates in Parkinson's disease brain. Acta Neuropathol Commun (2015)](https://pubmed.ncbi.nlm.nih.gov/26576979/)

[Kitsou E, et al. GPR37 modulates alpha-synuclein toxicity. Nat Commun (2024)](https://pubmed.ncbi.nlm.nih.gov/38582789/)

[Yang HJ, et al. GPR37 and protein quality control. Mol Neurobiol (2019)](https://pubmed.ncbi.nlm.nih.gov/31126982/)

[Zhang L, et al. GPR37 deficiency leads to neurodegeneration. Cell Death Dis (2018)](https://pubmed.ncbi.nlm.nih.gov/29371651/)

External Links

[NCBI Gene: GPR37](https://www.ncbi.nlm.nih.gov/gene/7102)
[UniProt: GPR37](https://www.uniprot.org/uniprot/O00163)
[OMIM: GPR37](https://www.omim.org/entry/603581)
[Ensembl: GPR37](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000170370)
[IUPHAR: GPR37](https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=200)

References

[Ma Q, et al. Oligodendrocytes drive neuroinflammation via the prosaposin-GPR37-IL-6 axis in Parkinson's disease. Nature (2024)](https://pubmed.ncbi.nlm.nih.gov/39913287/)

[Imai M, et al. GPR37 is a parkin substrate in Parkinson's disease. J Biol Chem (2004)](https://pubmed.ncbi.nlm.nih.gov/15316217/)

[Zhang S, et al. Parkin-mediated ubiquitination of GPR37 and its role in neurodegeneration. Neuron (2011)](https://pubmed.ncbi.nlm.nih.gov/21903076/)

[Dunham J, et al. GPR37 and ER stress in neurodegeneration. Cell Stress Chaperones (2019)](https://pubmed.ncbi.nlm.nih.gov/30605867/)

[Zhang Y, et al. GPR37 aggregates in Parkinson's disease brain. Acta Neuropathol Commun (2015)](https://pubmed.ncbi.nlm.nih.gov/26576979/)

[Kitsou E, et al. GPR37 modulates alpha-synuclein toxicity. Nat Commun (2024)](https://pubmed.ncbi.nlm.nih.gov/38582789/)

[Yang HJ, et al. GPR37 and protein quality control in neurons. Mol Neurobiol (2019)](https://pubmed.ncbi.nlm.nih.gov/31126982/)

[Zhang L, et al. GPR37 deficiency leads to neurodegeneration. Cell Death Dis (2018)](https://pubmed.ncbi.nlm.nih.gov/29371651/)

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

[Oligodendrocyte Protectin D1 Mimetic for Myelin Resolution](/hypothesis/h-f71a9791) — <span style="color:#ffd54f;font-weight:600">0.42</span> · Target: GPR37

Pathway Diagram

The following diagram shows the key molecular relationships involving GPR37 Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

GPR37

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-gpr37
kg_node_id	GPR37
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-2732b354f285
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-gpr37'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

80%

Debates

0

Incoming

16

Outgoing

33

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

GPR37 Gene

GPR37 Gene

Pathway Diagram

GPR37 Gene

Pathway Diagram

Overview

Gene Structure and Protein Architecture

Gene Organization

Protein Structure

Expression Pattern

Tissue Distribution

Cellular Expression

Subcellular Localization

Signaling Mechanisms

G Protein Coupling

Downstream Pathways

Non-G Protein Signaling

Role in Parkinson's Disease

1. Parkin Substrate ( Familial PD)

2. PSAP-GPR37-IL-6 Axis (2024 Nature Paper)

3. ER Stress and Protein Quality Control

4. Alpha-Synuclein Interaction

Other Disease Associations

Atypical Parkinsonism

Other Neurological Conditions

Therapeutic Implications

Targeting Strategies

Parkin-Enhancing Approaches

Anti-inflammatory Strategies

Animal Models

Knockout Mice (Gpr37-/-)

Transgenic Models

Interaction Network

Protein-Protein Interactions

Pathway Membership

Research Methods

Genetic Approaches

Molecular Biology

Functional Studies

Key Publications

See Also

External Links

References

Related Hypotheses

Pathway Diagram

💬 Discussion