The adenosine A2A receptor in the basal ganglia: Expression, heteromerization, functional selectivity and signalling

Adenosine is a neuroregulatory nucleoside that acts through four G protein-coupled receptors (GPCRs), A1, A2A, A2B and A3, which are widely expressed in cells of the nervous system. The A2A receptor (A2AR), the GPCR with the highest expression in the striatum, has a similar role to that of receptors for dopamine, one of the main neurotransmitters. Neuronal and glial A2ARs participate in the modulation of dopaminergic transmission and act in almost any action in which the basal ganglia is involved. This chapter revisits the expression of the A2AR in the basal ganglia in health and disease, and describes the diversity of signalling depending on whether the receptors are expressed as monomer or as heteromer. The A2AR can interact with other receptors as adenosine A1, dopamine D2, or cannabinoid CB1 to form heteromers with relevant functions in the basal ganglia. Heteromerization, with these and other GPCRs, provides diversity to A2AR-mediated signalling and to the modulation of neurotransmission. Thus, selective A2AR antagonists have neuroprotective potential acting directly on neurons, but also through modulation of glial cell activation, for example, by decreasing neuroinflammatory events that accompany neurodegenerative diseases. In fact, A2AR antagonists are safe and their potential in the therapy of Parkinson's disease has already led to the approval of one of them, istradefylline, in Japan and United States. The receptor also has a key role in reward circuits and, again, heteromers with dopamine receptors, but also with cannabinoid CB1 receptors, participate in the events triggered by drugs of abuse.