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      Experimental Evidence of A 2A–D 2 Receptor–Receptor Interactions in the Rat and Human Carotid Body

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          Abstract

          Adenosine A 2A receptors (A 2AR) and dopamine D 2 receptors (D 2R) 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 2AR and D 2R 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 2AR and D 2R 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 2AR–D 2R heterodimers by in situ proximity ligation assay (PLA). Our data by PLA analysis and tyrosine hydroxylase/S100 colocalization indicated the formation of A 2AR–D 2R heterodimers in type I and II cells of the CB; the presence of A 2AR–D 2R 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.

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          Most cited references101

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          G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives.

          Most evidence indicates that, as for family C G protein-coupled receptors (GPCRs), family A GPCRs form homo- and heteromers. Homodimers seem to be a predominant species, with potential dynamic formation of higher-order oligomers, particularly tetramers. Although monomeric GPCRs can activate G proteins, the pentameric structure constituted by one GPCR homodimer and one heterotrimeric G protein may provide a main functional unit, and oligomeric entities can be viewed as multiples of dimers. It still needs to be resolved if GPCR heteromers are preferentially heterodimers or if they are mostly constituted by heteromers of homodimers. Allosteric mechanisms determine a multiplicity of possible unique pharmacological properties of GPCR homomers and heteromers. Some general mechanisms seem to apply, particularly at the level of ligand-binding properties. In the frame of the dimer-cooperativity model, the two-state dimer model provides the most practical method to analyze ligand-GPCR interactions when considering receptor homomers. In addition to ligand-binding properties, unique properties for each GPCR oligomer emerge in relation to different intrinsic efficacy of ligands for different signaling pathways (functional selectivity). This gives a rationale for the use of GPCR oligomers, and particularly heteromers, as novel targets for drug development. Herein, we review the functional and pharmacological properties of GPCR oligomers and provide some guidelines for the application of discrete direct screening and high-throughput screening approaches to the discovery of receptor-heteromer selective compounds.
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            SH-SY5Y human neuroblastoma cell line: in vitro cell model of dopaminergic neurons in Parkinson's disease.

            To evaluate the human neuroblastoma SH-SY5Y cell line as an in vitro model of dopaminergic (DAergic) neurons for Parkinson's disease (PD) research and to determine the effect of differentiation on this cell model. The data of this review were selected from the original reports and reviews related to SH-SY5Y cells published in Chinese and foreign journals (Pubmed 1973 to 2009). After searching the literature, 60 articles were selected to address this review. The SH-SY5Y cell line has become a popular cell model for PD research because this cell line posses many characteristics of DAergic neurons. For example, these cells express tyrosine hydroxylase and dopamine-beta-hydroxylase, as well as the dopamine transporter. Moreover, this cell line can be differentiated into a functionally mature neuronal phenotype in the presence of various agents. Upon differentiation, SH-SY5Y cells stop proliferating and a constant cell number is subsequently maintained. However, different differentiating agents induce different neuronal phenotypes and biochemical changes. For example, retinoic acid induces differentiation toward a cholinergic neuronal phenotype and increases the susceptibility of SH-SY5Y cells to neurotoxins and neuroprotective agents, whereas treatment with retinoic acid followed by phorbol ester 12-O-tetradecanoylphorbol-13-acetate results in a DAergic neuronal phenotype and decreases the susceptibility of cells to neurotoxins and neuroprotective agents. Some differentiating agents also alter kinetics of 1-methyl-4-phenyl-pyridinium (MPP(+)) uptake, making SH-SY5Y cells more similar to primary mesencephalic neurons. Differentiated and undifferentiated SH-SY5Y cells have been widely used as a cell model of DAergic neurons for PD research. Some differentiating agents afford SH-SY5Y cells with more potential for studying neurotoxicity and neuroprotection and are thus more relevant to experimental PD research.
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              Peripheral chemoreceptors: function and plasticity of the carotid body.

              The discovery of the sensory nature of the carotid body dates back to the beginning of the 20th century. Following these seminal discoveries, research into carotid body mechanisms moved forward progressively through the 20th century, with many descriptions of the ultrastructure of the organ and stimulus-response measurements at the level of the whole organ. The later part of 20th century witnessed the first descriptions of the cellular responses and electrophysiology of isolated and cultured type I and type II cells, and there now exist a number of testable hypotheses of chemotransduction. The goal of this article is to provide a comprehensive review of current concepts on sensory transduction and transmission of the hypoxic stimulus at the carotid body with an emphasis on integrating cellular mechanisms with the whole organ responses and highlighting the gaps or discrepancies in our knowledge. It is increasingly evident that in addition to hypoxia, the carotid body responds to a wide variety of blood-borne stimuli, including reduced glucose and immune-related cytokines and we therefore also consider the evidence for a polymodal function of the carotid body and its implications. It is clear that the sensory function of the carotid body exhibits considerable plasticity in response to the chronic perturbations in environmental O2 that is associated with many physiological and pathological conditions. The mechanisms and consequences of carotid body plasticity in health and disease are discussed in the final sections of this article. © 2012 American Physiological Society
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                15 April 2021
                2021
                : 12
                : 645723
                Affiliations
                [1] 1Department of Neuroscience, Institute of Human Anatomy, University of Padova , Padua, Italy
                [2] 2Department of Physics and Astronomy “G. Galilei,” University of Padova , Padua, Italy
                [3] 3Institute of Pediatric Research Città della Speranza , Padua, Italy
                Author notes

                Edited by: Rodrigo Iturriaga, Pontificia Universidad Católica de Chile, Chile

                Reviewed by: Silvia V. Conde, New University of Lisbon, Portugal; Julio Alcayaga, University of Chile, Chile

                *Correspondence: Raffaele De Caro, raffaele.decaro@ 123456unipd.it

                This article was submitted to Integrative Physiology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2021.645723
                8082109
                29253b81-d2bb-498e-8445-17c058510bc2
                Copyright © 2021 Stocco, Sfriso, Borile, Contran, Barbon, Romanato, Macchi, Guidolin, De Caro and Porzionato.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 23 December 2020
                : 09 March 2021
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 101, Pages: 10, Words: 0
                Categories
                Physiology
                Brief Research Report

                Anatomy & Physiology
                carotid body,type i cells,adenosine a2a receptors,dopamine d2 receptors,heterodimes,in situ pla

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