P2RY14 Gene - Purinergic Receptor P2Y14

P2RY14 Gene

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">P2RY14 Gene</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>P2RY14</td></tr>
<tr><td><strong>Full Name</strong></td><td>Purinergic Receptor P2Y14</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>3q25.1</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td><a href="https://www.ncbi.nlm.nih.gov/gene/9939">9939</a></td></tr>
<tr><td><strong>UniProt ID</strong></td><td><a href="https://www.uniprot.org/uniprot/Q9HC97">Q9HC97</a></td></tr>
<tr><td><strong>Aliases</strong></td><td>GPR105, P2Y14, GPR158</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), [Multiple Sclerosis](/diseases/multiple-sclerosis), Stroke, Inflammatory diseases</td></tr>
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Overview

P2RY14 (Purinergic Receptor P2Y14) encodes a G-protein coupled receptor that responds to UDP-sugars (particularly UDP-glucose, UDP-galactose, and UDP-N-acetylglucosamine) and mediates immune and inflammatory responses. It is uniquely activated by extracellular nucleotides attached to sugar moieties, distinguishing it from other P2Y receptors that respond to nucleotides alone. P2RY14 is increasingly recognized as an important player in neuroinflammation and neurodegenerative diseases.

Gene Structure and Evolution

P2RY14 Gene

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">P2RY14 Gene</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>P2RY14</td></tr>
<tr><td><strong>Full Name</strong></td><td>Purinergic Receptor P2Y14</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>3q25.1</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td><a href="https://www.ncbi.nlm.nih.gov/gene/9939">9939</a></td></tr>
<tr><td><strong>UniProt ID</strong></td><td><a href="https://www.uniprot.org/uniprot/Q9HC97">Q9HC97</a></td></tr>
<tr><td><strong>Aliases</strong></td><td>GPR105, P2Y14, GPR158</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), [Multiple Sclerosis](/diseases/multiple-sclerosis), Stroke, Inflammatory diseases</td></tr>
</table>
</div>

Overview

P2RY14 (Purinergic Receptor P2Y14) encodes a G-protein coupled receptor that responds to UDP-sugars (particularly UDP-glucose, UDP-galactose, and UDP-N-acetylglucosamine) and mediates immune and inflammatory responses. It is uniquely activated by extracellular nucleotides attached to sugar moieties, distinguishing it from other P2Y receptors that respond to nucleotides alone. P2RY14 is increasingly recognized as an important player in neuroinflammation and neurodegenerative diseases.

Gene Structure and Evolution

P2RY14 is located on chromosome 3q25.1 and encodes a 336-amino acid GPCR belonging to the P2Y receptor family. The gene has evolved from an ancestral P2Y receptor through gene duplication and divergence, acquiring the unique ability to respond to UDP-sugars rather than simple nucleotides. This specialization likely evolved to respond to damage-associated molecular patterns (DAMPs) released during cellular stress and tissue injury.

Protein Structure and Pharmacology

Receptor Architecture

P2RY14 is a Class A GPCR with seven transmembrane domains:

• N-terminus: Extracellular, glycosylation sites
• Transmembrane domains: 7 α-helices crossing the membrane
• C-terminus: Intracellular, involved in G protein coupling and desensitization
• Disulfide bond: Conserved between extracellular loops

Ligand Recognition

P2RY14 has unique pharmacological properties:

Endogenous Agonists (in order of potency):

Selectivity:

• Unlike other P2Y receptors, P2RY14 does not respond to ATP, ADP, UTP, or UDP alone
• Requires the sugar moiety for activation
• This distinguishes it from P2RY2 (UTP/ATP responsive) and P2Y12 (ADP responsive)

Signaling Pathways

Normal Physiological Functions

Immune System Regulation

P2RY14 is highly expressed in immune tissues and regulates:

Mast Cell Function

• Inhibits IgE-mediated degranulation
• Modulates allergic responses
• Regulates histamine release

• Guides neutrophil migration to sites of inflammation
• Responds to damage-associated UDP-sugars
• Regulates inflammatory cell recruitment

• Modulates pro-inflammatory cytokine release
• Regulates NLRP3 inflammasome activity
• Controls chemokine production

Stem Cell Biology

P2RY14 plays a role in:

• Hematopoietic stem cell mobilization
• Mesenchymal stem cell function
• Stem cell niche regulation

Gastrointestinal Function

• High expression in enteric nervous system
• Modulates intestinal motility
• Involved in gut mucosal defense

Disease Associations

Alzheimer's Disease

P2RY14 is implicated in AD through multiple mechanisms:

Neuroinflammation

• P2RY14 is upregulated in AD brain
• Activated microglia express P2RY14
• UDP-sugar release from damaged cells activates P2RY14
• Creates feed-forward inflammatory loop

• [Aβ](/proteins/amyloid-beta) peptides can induce UDP-sugar release from neurons and glia
• P2RY14 activation amplifies microglial inflammatory response
• May contribute to chronic neuroinflammation

• P2RY14 modulates microglial phenotype
• Affects astrocyte reactivity
• Contributes to neurotoxic glial states

• P2RY14 antagonists may reduce neuroinflammation
• Preclinical studies show promise
• Brain-penetrant antagonists under development

Parkinson's Disease

In PD, P2RY14 is involved in:

Dopaminergic Neuron Degeneration

• P2RY14 expression increases in PD substantia nigra
• Contributes to inflammatory loss of dopaminergic neurons
• Microglial P2RY14 activation promotes neurotoxicity

• P2RY14 contributes to microglial activation
• Responds to α-synuclein-triggered UDP-sugar release
• Amplifies NLRP3 inflammasome activation

• P2RY14 in enteric nervous system may relate to PD gut symptoms
• α-Synuclein spread hypothesis involves gut neurons
• UDP-sugar signaling may participate in this pathway

Multiple Sclerosis

P2RY14 contributes to MS pathology:

EAE Models

• P2RY14 knockout mice show reduced EAE severity
• P2RY14 antagonists reduce demyelination
• Contributes to oligodendrocyte injury

• P2RY14 on microglia and astrocytes
• Drives pro-inflammatory cytokine production
• Promotes immune cell infiltration

Stroke and Brain Injury

In acute brain injury:

Damage-Associated Molecular Patterns

• Brain injury releases UDP-sugars
• P2RY14 activation contributes to secondary damage
• P2RY14 antagonists show neuroprotection in stroke models

• P2RY14 on activated microglia
• Contributes to blood-brain barrier breakdown
• Exacerbates neuronal injury

Expression Patterns

Tissue Distribution

P2RY14 is expressed in:

• Immune tissues: Spleen, thymus, bone marrow (highest)
• Brain: Cortex, hippocampus, cerebellum
• Gut: Enteric nervous system, intestinal epithelium
• Lung: Epithelial cells
• Platelets: Low expression

Brain Expression

In the brain, P2RY14 is expressed in:

• [Microglia](/cell-types/microglia) — activated microglia show high expression
• [Astrocytes](/cell-types/astrocytes) — particularly reactive astrocytes
• [Neurons](/cell-types/neurons) — lower expression, mainly in cortex
• [Oligodendrocytes](/cell-types/oligodendrocytes) — variable expression

Regulation

P2RY14 expression is regulated by:

• Inflammatory cytokines (IL-1β, TNF-α)
• LPS and pathogen-associated patterns
• Cellular stress and damage
• Glucocorticoids (suppression)

Molecular Pathways

Inflammasome Interaction

Key Interactions

| Interactor | Interaction Type | Functional Effect |
|------------|------------------|-------------------|
| UDP-glucose | Endogenous agonist | Receptor activation |
| β-arrestin | Arrestin recruitment | Desensitization, internalization |
| NLRP3 | Inflammasome | Inflammatory signaling |
| Gi/o proteins | G protein coupling | cAMP inhibition, βγ signaling |
| GRK | Kinase | Receptor phosphorylation |

Therapeutic Implications

Drug Development

Antagonists (selectivity for P2RY14):

• MRS2578: First selective antagonist (limited brain penetration)
• PPTN: Highly selective antagonist with in vivo efficacy
• ARB-242901: Brain-penetrant antagonist, preclinical
• Various scaffolds: In development

• UDP-glucose: Endogenous agonist
• MRS2905: Selective agonist (research use)

Clinical Status

• No P2RY14-targeted drugs approved yet
• P2RY14 antagonists in clinical trials for inflammatory diseases
• Preclinical data support neuroinflammatory applications
• Biomarker development underway

Challenges

• Brain-penetrant antagonists needed for CNS applications
• Selectivity over other P2Y receptors critical
• Understanding context-dependent functions
• Potential for immune system side effects

Research Directions

Current Research Areas

Future Directions

• Clinical trials for neuroinflammation
• Gene therapy approaches
• Combination therapies
• Personalized medicine approaches

Cross-References

• [Neuroinflammation Pathway](/mechanisms/neuroinflammation-pathway)
• [NLRP3 Inflammasome](/entities/nlrp3-inflammasome)
• [Gut-Brain Axis](/entities/gut-brain-axis)
• [Blood-Brain Barrier](/entities/blood-brain-barrier)
• [Cytokine Signaling](/mechanisms/cytokine-signaling)

See Also

• [P2RY14 Protein](/proteins/p2ry14-protein)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Multiple Sclerosis](/diseases/multiple-sclerosis)
• [Stroke](/diseases/stroke)
• [Purinergic Signaling](/mechanisms/purinergic-signaling)

External Links

• [NCBI Gene: P2RY14](https://www.ncbi.nlm.nih.gov/gene/?term=P2RY14)
• [GeneCards: P2RY14](https://www.genecards.org/cgi-bin/carddisp.pl?gene=P2RY14)
• [OMIM: P2RY14](https://omim.org/search?search=P2RY14)
• [Ensembl: P2RY14](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=P2RY14)
• [Allen Brain Atlas: P2RY14](https://human.brain-map.org/microarray/search/show?search_term=P2RY14)
• [UniProt: Q9HC97](https://www.uniprot.org/uniprot/Q9HC97)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving P2RY14 Gene - Purinergic Receptor P2Y14 discovered through SciDEX knowledge graph analysis: