The adenosine A_2A 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, A_2A, A_2B and A₃, which are widely expressed in cells of the nervous system. The A_2A receptor (A_2AR), 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 A_2ARs 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 A_2AR 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 A_2AR 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 A_2AR-mediated signalling and to the modulation of neurotransmission. Thus, selective A_2AR 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, A_2AR 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.