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

Abstract

Adenosine A2A receptors (A2AR) and dopamine D2 receptors (D2R) 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, A2AR and D2R 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 A2AR and D2R 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 A2AR–D2R heterodimers by in situ proximity ligation assay (PLA). Our data by PLA analysis and tyrosine hydroxylase/S100 colocalization indicated the formation of A2AR–D2R heterodimers in type I and II cells of the CB; the presence of A2AR–D2R 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.

Membrane Heteroreceptor Complexes as Second-Order Protein Modulators: A Novel Integrative Mechanism through Allosteric Receptor–Receptor Interactions

“…This important technique (PLA) was developed by Fredriksson, Gullberg, Söderberg and colleagues [58,59]. For recent work on the analysis and quantitation of the GPCR heterocomplexes with in situ PLA (see [57,[60][61][62][63][64][65][66][67][68][69][70][71]).…”

Receptor–Receptor Interactions and Glial Cell Functions with a Special Focus on G Protein-Coupled Receptors

“…RRI at the cell membrane have expanded our understanding of intercellular communication and they appeared to play a major role in the physiology and pathology of many districts of the body (see [30] for a review). Examples include the regulation of vascular homeostasis through the angiotensin II AT 1 receptor and its heterodimers [37], the chemoreceptor function of the carotid body [38] and the endocrine system, where a growing number of reports suggested receptor oligomerization as a significant aspect of endocrine regulation [39]. The possibility of pharmacological strategies targeting receptor heteromers has also been proposed in oncology [40].…”