Receptor–Receptor Interactions of G Protein-Coupled Receptors in the Carotid Body: A Working Hypothesis

Frontiers in Physiology

Luigi Agnati¹  Diego Guidolin²  Andrea Porzionato²  Veronica Macchi²  Raffaele De Caro²  Elena Stocco² 

[1]Department of Diagnostic, Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy

[2]Department of Neuroscience, University of Padua, Padua, Italy

关键词: carotid body;    GPCRs;    heteromers;    receptor mosaics;    hypoxia;    adenosine;   

DOI  :  10.3389/fphys.2018.00697

来源: DOAJ

【 摘 要 】

In the carotid body (CB), a wide series of neurotransmitters and neuromodulators have been identified. They are mainly produced and released by type I cells and act on many different ionotropic and metabotropic receptors located in afferent nerve fibers, type I and II cells. Most metabotropic receptors are G protein-coupled receptors (GPCRs). In other transfected or native cells, GPCRs have been demonstrated to establish physical receptor–receptor interactions (RRIs) with formation of homo/hetero-complexes (dimers or receptor mosaics) in a dynamic monomer/oligomer equilibrium. RRIs modulate ligand binding, signaling, and internalization of GPCR protomers and they are considered of relevance for physiology, pharmacology, and pathology of the nervous system. We hypothesize that RRI may also occur in the different structural elements of the CB (type I cells, type II cells, and afferent fibers), with potential implications in chemoreception, neuromodulation, and tissue plasticity. This ‘working hypothesis’ is supported by literature data reporting the contemporary expression, in type I cells, type II cells, or afferent terminals, of GPCRs which are able to physically interact with each other to form homo/hetero-complexes. Functional data about cross-talks in the CB between different neurotransmitters/neuromodulators also support the hypothesis. On the basis of the above findings, the most significant homo/hetero-complexes which could be postulated in the CB include receptors for dopamine, adenosine, ATP, opioids, histamine, serotonin, endothelin, galanin, GABA, cannabinoids, angiotensin, neurotensin, and melatonin. From a methodological point of view, future studies should demonstrate the colocalization in close proximity (less than 10 nm) of the above receptors, through biophysical (i.e., bioluminescence/fluorescence resonance energy transfer, protein-fragment complementation assay, total internal reflection fluorescence microscopy, fluorescence correlation spectroscopy and photoactivated localization microscopy, X-ray crystallography) or biochemical (co-immunoprecipitation, in situ proximity ligation assay) methods. Moreover, functional approaches will be able to show if ligand binding to one receptor produces changes in the biochemical characteristics (ligand recognition, decoding, and trafficking processes) of the other(s). Plasticity aspects would be also of interest, as development and environmental stimuli (chronic continuous or intermittent hypoxia) produce changes in the expression of certain receptors which could potentially invest the dynamic monomer/oligomer equilibrium of homo/hetero-complexes and the correlated functional implications.

【 授权许可】

Unknown