GPR35 is a G-protein coupled receptor that serves as the receptor for kynurenic acid (KYNA), a neuroactive metabolite of the tryptophan degradation pathway. GPR35 is widely expressed in the brain, particularly in microglia and neurons, where it mediates the neuroprotective effects of kynurenic acid. This receptor has emerged as a promising target for neurodegenerative disease therapy due to its roles in neuroinflammation, excitotoxicity, and oxidative stress. [1]
GPR35 is encoded by the GPR35 gene. Key features include:
GPR35 acts as a sensor of kynurenic acid levels in the brain, which increases during inflammation and neurodegeneration. The receptor mediates most of the neuroprotective effects of kynurenic acid. [2]
GPR35 agonists work through anti-inflammatory and neuroprotective signaling:
Anti-inflammatory Effects: GPR35 activation reduces pro-inflammatory cytokine production (TNF-α, IL-1β, IL-6) in microglia through cAMP-dependent signaling. [2:1]
Excitotoxicity Reduction: GPR35-mediated signaling reduces NMDA receptor overactivation, protecting against glutamate-induced excitotoxicity.
Antioxidant Effects: Activation promotes Nrf2 pathway activation and reduces oxidative stress.
Microglial Polarization: Shifts microglia from pro-inflammatory (M1) to neuroprotective (M2) phenotype.
GPR35 agonists may benefit AD through:
GPR35 is particularly relevant for PD:
GPR35 agonists are in various stages of development:
| Compound | Development Stage | Notes |
|---|---|---|
| Kynurenic acid | Natural product | Poor BBB penetration |
| Synthetic KYNA analogs | Preclinical | Improved brain penetration |
| Allosteric modulators | Discovery | Enhanced signaling |
| Property | Value |
|---|---|
| Target | GPR35 (Kynurenic Acid Receptor) |
| Drug Class | GPCR agonist |
| Endogenous Ligand | Kynurenic acid (KYNA) |
| Signaling | Gi-coupled, Gq-coupled |
Kynurenic acid and GPR35 in brain disorders. Mol Neurobiol. GPR35: the kynurenic acid receptor in neuroprotection. 2018. ↩︎
Wang J, et al. GPR35 activation reduces neuroinflammation in Parkinson's models. J Neuroinflammation. 2019. ↩︎ ↩︎