Modulation of neuroimmunity by adenosine and its receptors: Metabolism to mental illness

Adenosine is a pleiotropic bioactive with potent neuromodulatory properties. Due to its ability to easily cross the blood-brain barrier, it can act as a signaling molecule between the periphery and the brain. It functions through four (A1, A2A, A2B, and A3) cell surface G protein-coupled adenosine receptors (ARs) that are expressed in some combination on nearly all cells types within the CNS. By regulating the activity of adenylyl cyclase and changing the intracellular concentration of cAMP, adenosine can alter neuronal function and neurotransmission. A variety of illnesses related to metabolic dysregulation, such as type 1 diabetes and Alzheimer's disease, are associated with an elevated serum concentration of adenosine and a pathogenesis rooted in inflammation. This review describes the accepted physiologic function of adenosine in neurological disease and explores its new potential as a peripheral to central danger signal that can activate the neuroimmune system and contribute to symptoms of sickness and psychopathologies.