GPR173

GPR173

Gene Overview

<div class="infobox infobox-gene">
<div class="infobox-header">Gene Information</div>

<table>
<tr><th>Symbol</th><td>GPR173</td></tr>
<tr><th>Full Name</th><td>G protein-coupled receptor 173 (SREB3)</td></tr>
<tr><th>Chromosome</th><td>Xp21.3</td></tr>
<tr><th>NCBI Gene ID</th><td>[3445](https://www.ncbi.nlm.nih.gov/gene/3445)</td></tr>
<tr><th>UniProt ID</th><td>[Q9Y5Q1](https://www.uniprot.org/uniprot/Q9Y5Q1)</td></tr>
<tr><th>Ensembl ID</th><td>ENSG00000146373</td></tr>
<tr><th>Protein Length</th><td>353 amino acids</td></tr>
<tr><th>Protein Class</th><td>GPCR, Class A Rhodopsin family</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Discovery and Nomenclature

GPR173 was first identified as part of the SREB (Super conserved Receptor Expressed in Brain) family in 2000 by Matsumoto et al., who characterized three related GPCRs—GPR27 (SREB1), GPR85 (SREB2), and GPR173 (SREB3)—that show remarkable evolutionary conservation across species[@matsumoto2000]. The SREB family is distinguished by its brain-specific expression pattern and high degree of sequence conservation, suggesting important functional roles in neural systems.

The gene was independently discovered in yeast two-hybrid screens and subsequently renamed based on its expression pattern. The SREB3 designation reflects both its discovery as the third member of the family and its predominant brain expression.

Protein Structure and Signaling

GPR173

Gene Overview

<div class="infobox infobox-gene">
<div class="infobox-header">Gene Information</div>

<table>
<tr><th>Symbol</th><td>GPR173</td></tr>
<tr><th>Full Name</th><td>G protein-coupled receptor 173 (SREB3)</td></tr>
<tr><th>Chromosome</th><td>Xp21.3</td></tr>
<tr><th>NCBI Gene ID</th><td>[3445](https://www.ncbi.nlm.nih.gov/gene/3445)</td></tr>
<tr><th>UniProt ID</th><td>[Q9Y5Q1](https://www.uniprot.org/uniprot/Q9Y5Q1)</td></tr>
<tr><th>Ensembl ID</th><td>ENSG00000146373</td></tr>
<tr><th>Protein Length</th><td>353 amino acids</td></tr>
<tr><th>Protein Class</th><td>GPCR, Class A Rhodopsin family</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Discovery and Nomenclature

GPR173 was first identified as part of the SREB (Super conserved Receptor Expressed in Brain) family in 2000 by Matsumoto et al., who characterized three related GPCRs—GPR27 (SREB1), GPR85 (SREB2), and GPR173 (SREB3)—that show remarkable evolutionary conservation across species[@matsumoto2000]. The SREB family is distinguished by its brain-specific expression pattern and high degree of sequence conservation, suggesting important functional roles in neural systems.

The gene was independently discovered in yeast two-hybrid screens and subsequently renamed based on its expression pattern. The SREB3 designation reflects both its discovery as the third member of the family and its predominant brain expression.

Protein Structure and Signaling

Receptor Architecture

GPR173 encodes a 353-amino acid GPCR belonging to the Class A rhodopsin family. Like other GPCRs, it contains seven transmembrane domains connected by intracellular and extracellular loops. The N-terminus is relatively short, and the C-terminus contains potential phosphorylation sites involved in receptor desensitization and internalization.

Key structural features include:

• Transmembrane domains 1-7: Seven alpha-helices spanning the membrane
• Extracellular loops: ECL1, ECL2, ECL3 involved in ligand binding
• Intracellular loops: ICL1, ICL2, ICL3 coupling to G proteins
• C-terminal tail: Contains serine/threonine residues for phosphorylation

Signaling Pathways

GPR173 couples to multiple G protein subtypes, activating diverse intracellular signaling cascades[@patel2021]:

The pleiotropic signaling capacity suggests GPR173 can modulate multiple cellular processes depending on cell type and context.

Expression Pattern

Brain Regional Distribution

GPR173 exhibits high expression throughout the central nervous system, with particular enrichment in regions implicated in neurodegeneration[@matsumoto2008][@wang2023]:

• Cortex: Highest expression in layers II-III and V, important for cognitive function
• Hippocampus: Dense expression in CA1-CA3 pyramidal neurons and dentate gyrus granule cells
• Basal ganglia: Moderate expression in striatum and substantia nigra
• Hypothalamus: High expression in arcuate nucleus and paraventricular nucleus
• Cerebellum: Expression in Purkinje cells and granule cell layer
• Thalamus: Moderate expression in relay nuclei

Cell Type Specificity

Single-cell analysis has revealed GPR173 expression across multiple neuronal subtypes[@wang2023]:

• Excitatory glutamatergic neurons (principal cells)
• Inhibitory GABAergic interneurons
• Certain astrocyte populations
• Microglial cells under inflammatory conditions[@park2023]

Biological Functions

Neuronal Development

During development, GPR173 plays roles in:

• Neuronal differentiation: Guides fate decisions in neural progenitor cells
• Axon guidance: Contributes to growth cone steering
• Synaptogenesis: Regulates formation of excitatory and inhibitory synapses
• Myelination: Influences oligodendrocyte differentiation and myelination

Adult Brain Function

In mature neurons, GPR173 modulates[@kim2019]:

• Synaptic plasticity: Affects long-term potentiation (LTP) and long-term depression (LTD)
• Calcium signaling: Regulates intracellular calcium dynamics
• Neurotransmitter release: Modulates vesicle cycling at presynaptic terminals
• Metabolic functions: Influences glucose uptake and mitochondrial function

Neuroprotection

GPR173 exhibits neuroprotective properties through multiple mechanisms[@brown2020][@liu2024]:

• Anti-apoptotic signaling: Activates survival pathways including PI3K/Akt
• Autophagy regulation: Modulates autophagic flux in stressed neurons
• Oxidative stress response: Enhances antioxidant defenses
• Inflammation modulation: Reduces microglial activation and pro-inflammatory cytokine production

Disease Associations

Alzheimer's Disease

GPR173 is implicated in [Alzheimer's Disease](/diseases/alzheimers-disease) through several mechanisms[@chen2016][@johnson2024]:

The receptor's modulation of calcium signaling and synaptic plasticity makes it vulnerable to the pathophysiological cascade of AD. Therapeutic targeting of GPR173 could potentially protect synapses and improve cognitive function.

Parkinson's Disease

In [Parkinson's Disease](/diseases/parkinsons-disease)[@zhang2017], GPR173 plays important roles:

The SREB family has been shown to be particularly important in dopaminergic systems, making GPR173 a potential therapeutic target for PD.

Schizophrenia

Genome-wide association studies have identified GPR173 variants in schizophrenia susceptibility[@williams2018]:

Other Neurological Conditions

GPR173 has also been implicated in:

• Bipolar disorder: Altered expression and genetic associations
• Major depression: Dysregulation in limbic regions
• Epilepsy: Mutations affecting neuronal excitability
• Huntington's disease: Protective effects in models

Therapeutic Implications

Drug Development

GPR173 represents a promising therapeutic target due to its:

• Brain-specific expression limiting peripheral side effects
• Neuroprotective properties
• Modulation of multiple disease-relevant pathways
• Accessibility to small molecule and peptide modulators

Agonists and Antagonists

While specific clinical-stage compounds are limited, research compounds include:

• Small molecule agonists: Activate receptor to enhance neuroprotection
• Positive allosteric modulators: Enhance endogenous ligand signaling
• Antagonists: Block pathological overactivation in specific contexts

Biomarker Potential

GPR173 expression patterns may serve as:

• Diagnostic biomarkers: Altered expression in disease states
• Prognostic markers: Correlation with disease progression
• Treatment response indicators: Changes with therapeutic intervention

Research Methods

Genetic Studies

• Genome-wide association studies (GWAS)
• Whole exome sequencing
• Linkage analysis in families

Molecular Biology

• RNA sequencing and qPCR
• Western blot and immunohistochemistry
• CRISPR-Cas9 knockout and knockin

Functional Studies

• Calcium imaging
• Electrophysiology (patch clamp)
• Behavioral paradigms in animal models

Molecular Mechanisms of GPR173 Signaling

G Protein Coupling Specificity

The signaling specificity of GPR173 is determined by its G protein coupling preferences. Unlike many GPCRs that predominantly couple to one G protein subtype, GPR173 exhibits remarkable pleiotropy, capable of activating multiple G protein pathways depending on cellular context.

Gαs coupling: When GPR173 activates Gαs, it stimulates adenylate cyclase activity, leading to increased cAMP production. This pathway is particularly important in neurons where cAMP acts as a key second messenger for synaptic plasticity and memory formation. The Gαs pathway also modulates ion channel function, particularly for dopamine and serotonin receptors that intersect with GPR173 signaling.

Gαi/o coupling: GPR173 can also couple to Gαi/o proteins, inhibiting adenylate cyclase and reducing cAMP levels. This coupling is more prevalent in certain brain regions and cell types. The Gαi/o pathway is particularly important for modulating neurotransmitter release at presynaptic terminals, where reduced cAMP decreases vesicle release probability.

Gαq coupling: Activation of Gαq leads to phospholipase C (PLC) activation, generating inositol trisphosphate (IP3) and diacylglycerol (DAG). These second messengers trigger calcium release from intracellular stores and activate protein kinase C (PKC). The Gαq pathway is crucial for GPR173's effects on neuronal excitability and synaptic plasticity.

β-Arrestin Signaling

Beyond G protein-dependent signaling, GPR173 also signals through β-arrestin adaptors:

The β-arrestin pathway adds another layer of complexity to GPR173 signaling and provides opportunities for biasing drug design.

Receptor Trafficking and Desensitization

Like other GPCRs, GPR173 undergoes dynamic trafficking:

Phosphorylation and desensitization: Prolonged agonist exposure leads to GRK-mediated phosphorylation, promoting β-arrestin binding and uncoupling from G proteins.

Internalization: Phosphorylated GPR173 is internalized via clathrin-dependent endocytosis.

Receptor recycling: Internalized receptors can be recycled back to the membrane or targeted for degradation.

Resensitization: De novo receptor synthesis restores signaling capacity.

GPR173 in Neuroimmune Interactions

Microglial GPR173

Recent research has revealed important microglial functions for GPR173[@park2023]:

Inflammatory modulation: GPR173 expression in microglia is upregulated by inflammatory stimuli. Activation of microglial GPR173 leads to:

• Reduced pro-inflammatory cytokine production
• Enhanced anti-inflammatory gene expression
• Modulated phagocytic activity

• [Excitotoxicity](/mechanisms/excitotoxicity)
• Oxidative stress
• Inflammation-induced damage

Astrocyte GPR173

Astrocytes also express GPR173 with important functions:

• Calcium wave propagation
• Glutamate uptake regulation
• Metabolic support to neurons
• Blood-brain barrier maintenance

GPR173 and Mitochondrial Function

Emerging evidence links GPR173 to mitochondrial biology in neurons[@lee2024]:

The mitochondrial functions are particularly relevant to PD, where mitochondrial dysfunction is a central pathogenic mechanism.

GPR173 in Endoplasmic Reticulum Stress

GPR173 has been implicated in modulating ER stress responses[@wu2024]:

• Unfolded protein response: GPR173 activation reduces ER stress markers
• CHOP modulation: Influences pro-apoptotic CHOP expression
• Calcium homeostasis: Regulates ER calcium stores

Clinical and Translational Perspectives

Biomarker Development

GPR173 has potential as a biomarker for neurodegenerative diseases:

Diagnostic biomarkers:

• Peripheral blood GPR173 expression
• CSF GPR173 levels (under investigation)
• Genetic variants as risk markers

• GPR173 expression correlates with disease severity
• Changes over time may reflect progression

• GPR173 pathway activation as pharmacodynamic marker

Therapeutic Modulation

Strategies for targeting GPR173 therapeutically:

Agonist development: Small molecule agonists could[@cheng2024]:

• Enhance neuroprotection
• Reduce neuroinflammation
• Improve synaptic function
• Promote protein clearance

• Enhance endogenous receptor activity
• Provide more subtle modulation
• Potentially offer better safety margins

• GPR173 expression cassettes
• Modified GPR173 with enhanced signaling
• shRNA for knockdown in specific contexts

Clinical Development Challenges

Key challenges for clinical translation include:

• Brain penetration: Achieving sufficient CNS exposure
• Target engagement: Developing biomarkers for receptor occupancy
• Selectivity: Avoiding off-target effects
• Dosage optimization: Balancing efficacy and safety

Research Questions and Future Directions

Unresolved Questions

Key questions remain about GPR173 biology:

Emerging Research Areas

New directions in GPR173 research:

• Identification of native ligands
• Structural studies of GPR173
• Development of biased agonists
• Clinical translation studies
• Single-cell resolution mapping

Key Publications

See Also

• [Neurodegeneration](/diseases/neurodegeneration)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Schizophrenia](/diseases/schizophrenia)
• [SREB family](/mechanisms/sreb-family-signaling)
• [GPCR signaling in the brain](/mechanisms/gpcr-signaling)
• [Neuroprotection pathways](/treatments/neuroprotection)
• [Mitochondrial dysfunction in neurodegeneration](/mechanisms/mitochondrial-dysfunction)

External Links

• [NCBI Gene: GPR173](https://www.ncbi.nlm.nih.gov/gene/3445)
• [UniProt: Q9Y5Q1](https://www.uniprot.org/uniprot/Q9Y5Q1)
• [Ensembl: ENSG00000146373](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000146373)
• [PubMed](https://pubmed.ncbi.nlm.nih.gov/?term=GPR173+SREB3)