ADORA2A

The adenosine A2A receptor (ADORA2A), a G protein-coupled receptor (GPCR), mediates adenosine's anti-inflammatory and neuromodulatory effects by activating adenylyl cyclase through Gs proteins, elevating intracellular cAMP levels. Predominantly expressed in striatal neurons, immune cells, and coronary vessels, it modulates dopamine D2 receptor signaling in basal ganglia pathways critical for motor control. Its immunosuppressive role in tumor microenvironments involves inhibiting T-cell activation through cAMP-PKA signaling. Clinically, ADORA2A antagonists like istradefylline (approved for Parkinson's OFF episodes) target motor dysfunction by enhancing dopaminergic transmission. Over 20 investigational compounds, including dual A2A/A1 antagonists and partial agonists, are being explored for neurodegenerative diseases, cancer immunotherapy (e.g., AZD4635 combined with anti-PD-L1), and cardiac ischemia. Dysregulated A2AR signaling correlates with neuroinflammation in Alzheimer's, REM sleep behavior disorders, and chemotherapy-induced cognitive impairment.