P2RY13 Protein

P2RY13 Protein

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">P2RY13 Protein</th>
</tr>
<tr>
<td class="label">Domain</td>
<td>Amino Acids</td>
</tr>
<tr>
<td class="label">N-terminal extracellular domain</td>
<td>1-75</td>
</tr>
<tr>
<td class="label">Transmembrane domain 1 (TM1)</td>
<td>76-96</td>
</tr>
<tr>
<td class="label">Extracellular loop 1 (ECL1)</td>
<td>97-118</td>
</tr>
<tr>
<td class="label">Transmembrane domain 2 (TM2)</td>
<td>119-139</td>
</tr>
<tr>
<td class="label">Extracellular loop 2 (ECL2)</td>
<td>140-165</td>
</tr>
<tr>
<td class="label">Transmembrane domain 3 (TM3)</td>
<td>166-186</td>
</tr>
<tr>
<td class="label">Intracellular loop 1 (ICL1)</td>
<td>187-199</td>
</tr>
<tr>
<td class="label">Transmembrane domain 4 (TM4)</td>
<td>200-220</td>
</tr>
<tr>
<td class="label">Intracellular loop 2 (ICL2)</td>
<td>221-233</td>
</tr>
<tr>
<td class="label">Transmembrane domain 5 (TM5)</td>
<td>234-254</td>
</tr>
<tr>
<td class="label">Intracellular loop 3 (ICL3)</td>
<td>255-277</td>
</tr>
<tr>
<td class="label">Transmembrane domain 6 (TM6)</td>
<td>278-298</td>
</tr>
<tr>
<td class="label">Transmembrane domain 7 (TM7)</td>
<td>299-319</td>
</tr>
<tr>
<td class="label">C-terminal intracellular tail</td>
<td>320-370</td>
</tr>
<tr>
<td class="label">Region</td>

P2RY13 Protein

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">P2RY13 Protein</th>
</tr>
<tr>
<td class="label">Domain</td>
<td>Amino Acids</td>
</tr>
<tr>
<td class="label">N-terminal extracellular domain</td>
<td>1-75</td>
</tr>
<tr>
<td class="label">Transmembrane domain 1 (TM1)</td>
<td>76-96</td>
</tr>
<tr>
<td class="label">Extracellular loop 1 (ECL1)</td>
<td>97-118</td>
</tr>
<tr>
<td class="label">Transmembrane domain 2 (TM2)</td>
<td>119-139</td>
</tr>
<tr>
<td class="label">Extracellular loop 2 (ECL2)</td>
<td>140-165</td>
</tr>
<tr>
<td class="label">Transmembrane domain 3 (TM3)</td>
<td>166-186</td>
</tr>
<tr>
<td class="label">Intracellular loop 1 (ICL1)</td>
<td>187-199</td>
</tr>
<tr>
<td class="label">Transmembrane domain 4 (TM4)</td>
<td>200-220</td>
</tr>
<tr>
<td class="label">Intracellular loop 2 (ICL2)</td>
<td>221-233</td>
</tr>
<tr>
<td class="label">Transmembrane domain 5 (TM5)</td>
<td>234-254</td>
</tr>
<tr>
<td class="label">Intracellular loop 3 (ICL3)</td>
<td>255-277</td>
</tr>
<tr>
<td class="label">Transmembrane domain 6 (TM6)</td>
<td>278-298</td>
</tr>
<tr>
<td class="label">Transmembrane domain 7 (TM7)</td>
<td>299-319</td>
</tr>
<tr>
<td class="label">C-terminal intracellular tail</td>
<td>320-370</td>
</tr>
<tr>
<td class="label">Region</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Hippocampus</td>
<td>High</td>
</tr>
<tr>
<td class="label">Cortex</td>
<td>High</td>
</tr>
<tr>
<td class="label">Striatum</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Thalamus</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Cerebellum</td>
<td>Low-Moderate</td>
</tr>
<tr>
<td class="label">Brainstem</td>
<td>Variable</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">ATPγS</td>
<td>P2RY13 agonist</td>
</tr>
<tr>
<td class="label">2-MeSADP</td>
<td>P2RY13 agonist</td>
</tr>
<tr>
<td class="label">MRS2211</td>
<td>P2RY13 agonist</td>
</tr>
<tr>
<td class="label">MRS2395</td>
<td>P2RY13 agonist</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Selectivity</td>
</tr>
<tr>
<td class="label">MRS2212</td>
<td>P2RY13 antagonist</td>
</tr>
<tr>
<td class="label">Tetrabutylammonium</td>
<td>P2RY13 antagonist</td>
</tr>
<tr>
<td class="label">Suramin derivatives</td>
<td>Varying</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/atherosclerosis" style="color:#ef9a9a">Atherosclerosis</a>, <a href="/wiki/cardiovascular" style="color:#ef9a9a">Cardiovascular</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">9 edges</a></td>
</tr>
</table>

P2RY13 (Purinergic Receptor P2Y13), also known as P2Y13, is a G protein-coupled receptor (GPCR) belonging to the P2Y receptor family that responds to extracellular nucleotides, primarily ATP and ADP. The receptor plays a critical role in modulating neuroinflammatory responses, microglial phagocytosis, and cellular homeostasis in the central nervous system. P2RY13 has emerged as a significant therapeutic target for neurodegenerative diseases due to its strategic position in microglial function and its involvement in the clearance of pathological protein aggregates.

The receptor is encoded by the P2RY13 gene (Gene ID: 53833), located on chromosome 3q25.32 in humans. It is approximately 42 kDa in molecular weight and consists of 370 amino acids. P2RY13 is primarily expressed in immune cells, particularly microglia in the brain, where it serves as a key sensor of extracellular ATP/ADP released during cellular stress, inflammation, or neuronal damage.

Gene and Protein Structure

Gene Organization

The P2RY13 gene is situated on human chromosome 3q25.32, spanning approximately 6.5 kb of genomic DNA. The gene consists of two exons that encode the complete coding sequence. The promoter region contains several regulatory elements that control tissue-specific and stimulus-dependent expression:

• NF-κB binding sites: Allow inflammation-responsive upregulation
• AP-1 elements: Mediate stress-induced expression
• STAT binding sites: Enable cytokine-responsive regulation
• cAMP response elements (CRE): Allow activity-dependent modulation

Protein Architecture

P2RY13 is a class A GPCR with seven transmembrane domains:

The receptor contains conserved motifs characteristic of P2Y receptors, including the DRY motif (Arg-Arg-Tyr) at the boundary of TM3 and ICL2, which is essential for G protein coupling.

Post-translational Modifications

• N-linked glycosylation: At Asn residues in the N-terminal domain (positions 18, 32, 51)
• Disulfide bonds: Between conserved cysteine residues in ECL1 and ECL2
• Palmitoylation: At cysteine residues in the C-terminal tail for membrane anchoring
• Phosphorylation: At serine/threonine residues in ICL3 and C-terminal tail for desensitization

Normal Physiological Function

Purinergic Signaling in the Brain

P2RY13 is a key component of the purinergic signaling system in the brain: [@burnstock2017]

• Synaptic activity and neurotransmitter release
• Cellular stress and damage
• Inflammation and immune activation
• Metabolic stress

• P2RY13 responds to both ATP and ADP
• Activation triggers intracellular signaling cascades
• Different nucleotides can produce different effects

• Ectonucleotidase degradation (CD39, CD73)
• Receptor internalization
• Receptor desensitization

Microglial Function Modulation

P2RY13 plays a central role in microglial biology: [@mildner2016]

Phagocytosis Regulation

• Pro-phagocytic signaling: P2RY13 activation enhances microglial phagocytosis
• ATP/ADP as "find-me" signals: Extracellular nucleotides attract microglia to sites of damage
• Clearance of debris: Essential for removing dead cells and protein aggregates
• Synaptic pruning: Regulates developmental and activity-dependent synaptic remodeling

Cytokine and Chemokine Release

• Modulates inflammatory responses: P2RY13 signaling affects cytokine production
• Anti-inflammatory effects: In some contexts, P2RY13 activation reduces pro-inflammatory cytokine release
• Chemotactic effects: Guides microglial migration toward injury sites

Migration and Chemotaxis

• ATP gradient sensing: Microglia follow ATP/ADP gradients to damaged regions
• Process extension: P2RY13 contributes to directed process motility
• Border maintenance: Helps establish and maintain protective microglial borders

Brain Region Distribution

Role in Neurodegenerative Diseases

Alzheimer's Disease

P2RY13 is significantly implicated in Alzheimer's disease pathogenesis: [@yang2020]

Amyloid-beta Clearance

• Enhanced phagocytosis: P2RY13 activation increases microglial clearance of Aβ plaques
• ATP release from Aβ: Amyloid-beta stimulates ATP release from neurons and astrocytes
• Receptor upregulation: P2RY13 expression increases in AD brain, particularly in plaque-associated microglia
• Therapeutic potential: P2RY13 agonists may enhance Aβ clearance

Tau Pathology

P2RY13 also modulates tau pathology: [@park2023]

• Microglial activation: P2RY13 affects tau-induced neuroinflammation
• Clearance mechanisms: May influence tau uptake and degradation
• Neuronal protection: Agonist activation reduces tau-induced毒性

Neuroinflammation

• Dual role: P2RY13 can promote both pro- and anti-inflammatory responses
• Context-dependent effects: Depend on disease stage and microglial activation state
• Cytokine modulation: Affects production of IL-1β, TNF-α, and IL-6

Parkinson's Disease

P2RY13 contributes to Parkinson's disease pathophysiology: [@zhang2022]

Alpha-synuclein Clearance

• Phagocytic enhancement: P2RY13 activation promotes microglial uptake of α-synuclein aggregates
• Neuronal protection: Reduces extracellular α-synuclein spreading
• Inflammation modulation: Affects the neuroinflammatory environment in the substantia nigra

Dopaminergic Neuron Protection

• Anti-inflammatory effects: P2RY13 signaling can reduce microglial toxicity to dopaminergic neurons
• Metabolic support: May improve neuronal metabolic function
• Mitochondrial protection: Reduced oxidative stress on neurons

Amyotrophic Lateral Sclerosis

P2RY13 plays a role in ALS pathophysiology: [@choi2022]

• Microglial activation state: P2RY13 modulates the transition between protective and toxic microglial phenotypes
• Motor neuron protection: Agonist treatment reduces microglial-mediated damage
• Disease progression: P2RY13 expression correlates with disease progression in mouse models

Multiple Sclerosis

P2RY13 is involved in demyelinating disease processes: [@liu2023]

• Immune cell trafficking: Regulates immune cell infiltration into the CNS
• Demyelination: Affects oligodendrocyte survival and remyelination
• Inflammatory demyelination: Modulates the autoimmune response

Other Neurodegenerative Conditions

Neuropathic Pain

P2RY13 contributes to chronic pain states: [@campos2020]

• Sensory neuron modulation: Affects dorsal root ganglion neuron function
• Inflammatory pain: Modulates pain signaling in peripheral and central nervous systems
• Therapeutic targeting: P2RY13 modulators may reduce chronic pain

Traumatic Brain Injury

P2RY13 is activated following brain trauma: [@abdelmagid2022]

• Damage detection: ATP release serves as a damage signal
• Inflammatory response: Modulates post-traumatic neuroinflammation
• Repair processes: Affects debris clearance and repair mechanisms

Therapeutic Targeting

Agonists

Positive allosteric modulators are under development for enhanced receptor activation.

Antagonists

Therapeutic Strategies

Challenges

Related Pathways

Purinergic Signaling Cascade

Cross-talk with Other Receptors

• P2RY12: Co-expressed in microglia, functional interactions
• P2RX7: ATP-gated channel, synergistic signaling
• TREM2: Microglial activation receptor, cooperates in phagocytosis
• CX3CR1: Fractalkine receptor, complementary functions

Biomarker Potential

P2RY13 has potential as a biomarker and therapeutic target:

• Diagnostic marker: P2RY13 expression may indicate microglial activation state
• Prognostic value: Correlates with disease severity
• Therapeutic response: Changes in P2RY13 signaling may predict treatment response
• Target engagement: PET ligands for P2RY13 may allow in vivo imaging

Key Publications

See Also

• [P2RY13 Gene](/genes/p2ry13)
• [Purinergic Signaling](/mechanisms/purinergic-signaling)
• [Microglia in Neurodegeneration](/cell-types/microglia-neuroinflammation)
• [Neuroinflammation](/mechanisms/neuroinflammation-pathway)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
• [P2Y Receptor Family](/mechanisms/p2y-receptor-signaling)

External Links

• [UniProt: Q9NZR8](https://www.uniprot.org/uniprot/Q9NZR8)
• [IUPHAR: P2Y13](https://www.guidetopharmacology.org/GRAC/receptorDisplayForward?receptorId=235)
• [GeneCards: P2RY13](https://www.genecards.org/cgi-bin/carddisp.pl?gene=P2RY13)
• [OMIM: 607458](https://omim.org/entry/607458)

References