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.
Highlights
Type I cells produce several neurotransmitters [e.g., dopamine, noradrenaline, adrenaline, acetylcholine, serotonin, adenosine, adenosine 5 -triphosphate (ATP)] and neuromodulators (Varas et al, 2003; Iturriaga and Alcayaga, 2004; Porzionato et al, 2008), in turn acting in an autocrine/paracrine manner on a broad spectrum of different ionotropic/metabotropic receptors located in afferent nerve fibers, type I cells, and type II cells, these latter showing a role in the coordination of chemosensory transduction (Nurse, 2014; Porzionato et al, 2018; Stocco et al, 2020)
Adenosine A2A receptors (A2AR) and dopamine D2 receptors (D2R) were identified through immunohistochemistry in both rat and human carotid body (CB) (Figure 1)
proximity ligation assay (PLA) is an antibody-based method to detect biomolecules in physical proximity, and it is recognized as an important experimental approach to demonstrate physical receptor interactions (RRIs) when native molecules are localized within a radius of 0–16 nm, a distance considered crucial for heteromer formation
Summary
The carotid bodies (CBs) are chemosensory organs located at the bifurcations of the common carotid arteries with a critical role in maintaining homeostasis during both development/aging (Di Giulio, 2018; Sacramento et al, 2019) and environmental variations (e.g., levels of O2, CO2, and arterial blood pH) (Iturriaga and Alcayaga, 2004; Iturriaga et al, 2016; Prabhakar and Peng, 2017; Di Giulio, 2018; Iturriaga, 2018) with a sensing function with respect to metabolic factors (Porzionato et al, 2011; Conde et al, 2018; Cunha-Guimaraes et al, 2020; Sacramento et al, 2020).The CB regulatory function is strictly related to its specific organization. Type I cells produce several neurotransmitters [e.g., dopamine, noradrenaline, adrenaline, acetylcholine, serotonin, adenosine, adenosine 5 -triphosphate (ATP)] and neuromodulators (e.g., enkephalins, neuropeptide Y, calcitonin gene-related peptide, galanin, endothelins, bombesin, adrenomedullin, kisspeptins, leptin) (Varas et al, 2003; Iturriaga and Alcayaga, 2004; Porzionato et al, 2008), in turn acting in an autocrine/paracrine manner on a broad spectrum of different ionotropic/metabotropic receptors located in afferent nerve fibers, type I cells, and type II cells, these latter showing a role in the coordination of chemosensory transduction (Nurse, 2014; Porzionato et al, 2018; Stocco et al, 2020) Among these receptors, some metabotropic G protein-coupled receptors (GPCRs) (e.g., A2A, D1/2, H1/2/3, M1/2, 5-HT2A, and others) are involved; in particular, A2A and D2 have attracted the attention of many researchers, resulting among the most studied GPCRs (Aldossary et al, 2020)
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