GPR65, also known as TDAG8 (T-cell death-associated gene 8), is a proton-sensing G-protein coupled receptor that plays crucial roles in immune regulation and cellular homeostasis. Originally identified as a gene induced during T-cell apoptosis, GPR65 is now recognized as an important modulator of neuroinflammation and a potential therapeutic target for neurodegenerative diseases. [1]
GPR65 is encoded by the GPR65 gene and belongs to the proton-sensing GPCR family (including GPR4, GPR68, GPR132). Key characteristics include:
The receptor acts as a sensor of tissue acidification, which occurs during inflammation and ischemia. [2]
GPR65 modulators exert neuroprotective effects through acid-sensing and immune modulation:
Microglial Modulation: GPR65 activation shifts microglia from pro-inflammatory (M1) to anti-inflammatory (M2) phenotype, reducing neuroinflammation. [1:1]
Acid Sensing: In inflamed or ischemic brain tissue, GPR65 senses the acidic environment and activates protective signaling.
cAMP Regulation: The dual G-protein coupling allows context-dependent signaling modulation.
T-cell Regulation: GPR65 on peripheral immune cells may reduce CNS infiltration of inflammatory cells.
GPR65 modulators may benefit AD through:
GPR65 is particularly relevant for PD:
GPR65 modulators are in early development. Key approaches include:
| Approach | Development Stage | Notes |
|---|---|---|
| Small molecule agonists | Preclinical | Mimic acidosis signaling |
| Positive allosteric modulators | Discovery | Enhance proton sensitivity |
| GPR65 gene therapy | Discovery | Sustained modulation |
| Property | Value |
|---|---|
| Target | GPR65 (TDAG8, GPCR13) |
| Drug Class | Proton-sensing GPCR modulator |
| Endogenous Ligand | Protons (H⁺) |
| Signaling | Gs/Gi-coupled, context-dependent |
GPR65 remains an emerging target. Key challenges include:
Tomlinson MG, et al. GPR65 in microglial activation and neuroinflammation. J Neuroinflammation. 2019. ↩︎ ↩︎
Liu B, et al. Proton-sensing GPCRs in neuroprotection and disease. Pharmacol Rev. 2017. ↩︎
Ryoo N, et al. Targeting GPR65 for Parkinson's disease therapy. NPJ Parkinsons Dis. 2021. ↩︎