The P2Y14 receptor is a G-protein coupled receptor that responds to UDP-glucose and other sugar nucleotides. It is widely expressed in the brain on astrocytes, microglia, and neurons, where it mediates glial communication and inflammatory responses. P2Y14 receptor antagonists represent a novel approach to modulate neuroinflammation in neurodegenerative diseases. [1]
P2Y14 is encoded by the P2RY14 gene. Key features include:
P2Y14 is unique among P2Y receptors as it responds to sugar nucleotides rather than nucleotides, suggesting roles in cellular metabolism and stress responses. [2]
P2Y14 antagonists work through modulation of glial signaling:
Glial Communication: P2Y14 mediates UDP-glucose release from stressed cells, triggering inflammatory responses in neighboring glia. Antagonists break this cascade. [1:1]
Inflammatory Modulation: P2Y14 signaling promotes pro-inflammatory cytokine production in microglia and astrocytes; antagonists reduce this.
Astrocyte-Neuron Crosstalk: P2Y14 on astrocytes affects neuronal support functions; modulation may improve neuronal survival.
Cell Stress Response: UDP-glucose release signals cellular stress; blocking P2Y14 reduces harmful inflammatory amplification.
P2Y14 antagonists may benefit AD through:
P2Y14 antagonists are relevant for PD:
P2Y14 antagonists are in early development:
| Compound | Development Stage | Notes |
|---|---|---|
| PPTN | Research compound | First selective antagonist |
| MRS4690 | Research compound | Improved selectivity |
| Selective antagonists | Preclinical | Optimizing brain penetration |
| Property | Value |
|---|---|
| Target | P2Y14 (P2RY14) |
| Drug Class | P2Y14 receptor antagonist |
| Endogenous Ligand | UDP-glucose, UDP-galactose |
| Signaling | Gi-coupled |
P2Y14 is an emerging target:
Abbracchio MP, et al. P2Y14 receptor: a novel target for neuroinflammation. Purinergic Signal. 2018. ↩︎ ↩︎
Jacobson KA, et al. UDP-glucose signaling through P2Y14 in glial cells. Glia. 2020. ↩︎