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Adenosine A 2A  receptors (A 2A R) and dopamine D 2  receptors (D 2 R) are known to be involved in the physiological response to hypoxia, and their expression/activity may be modulated by chronic sustained or intermittent hypoxia. To date, A 2A R and D 2 R can form transient physical receptor–receptor interactions (RRIs) giving rise to a dynamic equilibrium able to influence ligand binding and signaling, as demonstrated in different native tissues and transfected mammalian cell systems. Given the presence of A 2A R and D 2 R in type I cells, type II cells, and afferent nerve terminals of the carotid body (CB), the aim of this work was to demonstrate here, for the first time, the existence of A 2A R–D 2 R heterodimers by  in situ  proximity ligation assay (PLA). Our data by PLA analysis and tyrosine hydroxylase/S100 colocalization indicated the formation of A 2A R–D 2 R heterodimers in type I and II cells of the CB; the presence of A 2A R–D 2 R heterodimers also in afferent terminals is also suggested by PLA signal distribution. RRIs could play a role in CB dynamic modifications and plasticity in response to development/aging and environmental stimuli, including chronic intermittent/sustained hypoxia. Exploring other RRIs will allow for a broad comprehension of the regulative mechanisms these interactions preside over, with also possible clinical implications.

Experimental Evidence of A2A–D2 Receptor–Receptor Interactions in the Rat and Human Carotid Body