Cannabidiol negatively modulates adenosine A_2A receptor functioning in living cells

Objectives: Cannabidiol (CBD) is a phytocannabinoid with great potential in clinical applications. The mechanism(s) of action of CBD require further investigation. Previous studies suggested that adenosine A_2A receptors (A_2ARs) could play a role in CBD-induced effects. Here, we evaluated the ability of CBD to modify the function of A_2AR.

Methods: We used HEK-293T cells transfected with the cDNA encoding the human A_2AR and Gαs protein, both modified to perform bioluminescence-based assays. We first assessed the effect of CBD on A_2AR ligand binding using an A_2AR NanoLuciferase sensor. Next, we evaluated whether CBD modified A_2AR coupling to mini-Gαs proteins using the NanoBiT™ assay. Finally, we further assessed CBD effects on A_2AR intrinsic activity by recording agonist-induced cAMP accumulation.

Results: CBD did not bind orthosterically to A_2AR but reduced the coupling of A_2AR to Gαs protein and the subsequent generation of cAMP.

Conclusion: CBD negatively modulates A_2AR functioning.