Limonene, a natural cyclic terpene, is an agonistic ligand for adenosine A_2A receptors

Limonene is a major aromatic compound in essential oils extracted from citrus rind. The application of limonene, especially in aromatherapy, has expanded significantly, but its potential effects on cellular metabolism have been elusive. We found that limonene directly binds to the adenosine A_2A receptor, which may induce sedative effects. Results from an in vitro radioligand binding assay showed that limonene exhibits selective affinity to A_2A receptors. In addition, limonene increased cytosolic cAMP concentration and induced activation of protein kinase A and phosphorylation of cAMP-response element-binding protein in Chinese hamster ovary cells transfected with the human adenosine A_2A receptor gene. Limonene also increased cytosolic calcium concentration, which can be achieved by the activation of adenosine A_2A receptors. These findings suggest that limonene can act as a ligand and an agonist for adenosine A_2A receptors.