Journal articles on the topic 'Adenosine receptors, A1, A2B'
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Dubey, Raghvendra K., Delbert G. Gillespie, and Edwin K. Jackson. "A2B Adenosine Receptors Mediate the Anti-Mitogenic Effects of Adenosine in Cardiac Fibroblasts." Hypertension 36, suppl_1 (October 2000): 708. http://dx.doi.org/10.1161/hyp.36.suppl_1.708-b.
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P85 Adenosine inhibits growth of CFs; however, the adenosine receptor subtype that mediates this anti-mitogenic effect remains undefined. Using specific ADE receptor antagonists and agonists and antisense oligonucleotides (OLIGO) against A2B receptors, we investigated the role of A2B receptors in inhibiting cardiac fibroblast growth. PDGF (25ng/ml)-induced DNA synthesis, cell number and collagen synthesis in CFs were inhibited by A2 (chloroadenosine [Cl-Ad]and MECA), but not by A1 (CPA), A2a ( CGS21680 ) or A3 (AB-MECA),receptor agonists.The inhibitory effects of 1μM MECA and Cl-Ad were reversed by A1/A2 (DPSPX; 10nM), but not by A1 (DPCPX; 10nM), receptor antagonists. In CFs treated with antisense, but not sense or scrambled, OLIGOs to the A2B receptor, both basal and PDGF-induced DNA synthesis was enhanced by 70±4% and 64±5% respectively. Moreover, the inhibitory effects of Cl-Ad and MECA were completely abolished in CFs treated with antisense, but not sense and scrambled, OLIGOs. In conclusion, A2B receptors mediate the anti-mitogenic effects of adenosine suggesting that A2B receptors are importantly involved in the regulation of CF biology. Thus, A2B receptors may play a critical role in regulating cardiac remodeling associated with CF proliferation.
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Borgland, Stephanie L., Maria Castañón, Walter Spevak, and Fiona E. Parkinson. "Effects of propentofylline on adenosine receptor activity in Chinese hamster ovary cell lines transfected with human A1, A2A, or A2B receptors and a luciferase reporter gene." Canadian Journal of Physiology and Pharmacology 76, no. 12 (December 1, 1998): 1132–38. http://dx.doi.org/10.1139/y98-143.
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Propentofylline is neuroprotective in vivo, but its mechanism of action is not completely understood. Previously, propentofylline was shown to block adenosine transport processes, to inhibit three adenosine receptor subtypes, and to inhibit cAMP phosphodiesterase. We tested the effect of propentofylline on adenosine receptor function in Chinese hamster ovary (CHO) cells transfected with human adenosine A1, A2A, or A2B receptors and a luciferase reporter gene under control of a promoter sequence containing several copies of the cAMP response element. We investigated the concentration-dependent inhibitory effects of propentofylline on cAMP phosphodiesterase, adenosine transport processes, and adenosine A1, A2A, and A2B receptors. At concentrations >= 1 mM, propentofylline increased luciferase activity probably as a result of inhibition of cAMP phosphodiesterase. Inhibition of [3H]adenosine uptake by propentofylline was concentration dependent, with IC50 values of 37-39 µM for the three cell types. Agonist-activated adenosine A1 receptors were antagonized by 100 µM propentofylline, but inhibition of agonist-stimulated A2A or A2B receptors was not observed. In contrast, A1 and A2A receptor mediated effects of adenosine were enhanced by propentofylline at concentrations of 1 and 100 µM, respectively. These data indicate that the net effects of propentofylline in vivo will be dependent on the concentrations of propentofylline and adenosine available and on the subtypes of adenosine receptors, phosphodiesterases, and nucleoside transporters present.Key words: adenosine receptors, nucleoside transport, propentofylline.
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Wolska, Nina, and Marcin Rozalski. "Blood Platelet Adenosine Receptors as Potential Targets for Anti-Platelet Therapy." International Journal of Molecular Sciences 20, no. 21 (November 3, 2019): 5475. http://dx.doi.org/10.3390/ijms20215475.
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Adenosine receptors are a subfamily of highly-conserved G-protein coupled receptors. They are found in the membranes of various human cells and play many physiological functions. Blood platelets express two (A2A and A2B) of the four known adenosine receptor subtypes (A1, A2A, A2B, and A3). Agonization of these receptors results in an enhanced intracellular cAMP and the inhibition of platelet activation and aggregation. Therefore, adenosine receptors A2A and A2B could be targets for anti-platelet therapy, especially under circumstances when classic therapy based on antagonizing the purinergic receptor P2Y12 is insufficient or problematic. Apart from adenosine, there is a group of synthetic, selective, longer-lasting agonists of A2A and A2B receptors reported in the literature. This group includes agonists with good selectivity for A2A or A2B receptors, as well as non-selective compounds that activate more than one type of adenosine receptor. Chemically, most A2A and A2B adenosine receptor agonists are adenosine analogues, with either adenine or ribose substituted by single or multiple foreign substituents. However, a group of non-adenosine derivative agonists has also been described. This review aims to systematically describe known agonists of A2A and A2B receptors and review the available literature data on their effects on platelet function.
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Feng, Ming-Guo, and L. Gabriel Navar. "Afferent arteriolar vasodilator effect of adenosine predominantly involves adenosine A2B receptor activation." American Journal of Physiology-Renal Physiology 299, no. 2 (August 2010): F310—F315. http://dx.doi.org/10.1152/ajprenal.00149.2010.
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Adenosine is an important paracrine agent regulating renal vascular tone via adenosine A1 and A2 receptors. While A2B receptor message and protein have been localized to preglomerular vessels, functional evidence on the role of A2B receptors in mediating the vasodilator action of adenosine on afferent arterioles is not available. The present study determined the role of A2B receptors in mediating the afferent arteriolar dilation and compared the effects of A2B and A2A receptor blockade on afferent arterioles. We used the rat in vitro blood-perfused juxtamedullary nephron technique combined with videomicroscopy. Single afferent arterioles of Sprague-Dawley rats were visualized and superfused with solutions containing adenosine or adenosine A2 receptor agonist (CV-1808) along with adenosine A2B and A2A receptor blockers. Adenosine (10 μmol/l) caused modest constriction and subsequent superfusion with SCH-58261 (SCH), an A2A receptor blocker, at concentrations up 10 μmol/l elicited only slight additional decreases in afferent arteriolar diameter with maximum effect at a concentration of 1 μmol/l (−11.0 ± 2.5%, n = 6, P < 0.05). However, superfusion of adenosine-treated vessels with MRS-1754 (MRS), an A2B receptor blocker, elicited greater decreases in afferent arteriolar diameter (−26.0 ± 4.7%, n = 5, P < 0.01). SCH did not significantly augment the adenosine-mediated afferent constriction elicited by MRS; however, adding MRS after SCH caused further significant vasoconstriction. Superfusion with CV-1808 dilated afferent arterioles (17.2 ± 2.4%, n = 6, P < 0.01). This effect was markedly attenuated by MRS (−22.6 ± 2.0%, n = 5, P < 0.01) but only slightly reduced by SCH (−9.0 ± 1.1%, n = 5, P < 0.05) and completely prevented by adding MRS after SCH (−24.7 ± 1.8%, n = 5, P < 0.01). These results indicate that, while both A2A and A2B receptors are functionally expressed in juxtamedullary afferent arterioles, the powerful vasodilating action of adenosine predominantly involves A2B receptor activation, which counteracts A1 receptor-mediated vasoconstriction.
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Zhan, Enbo, Victoria J. McIntosh, and Robert D. Lasley. "Adenosine A2A and A2B receptors are both required for adenosine A1 receptor-mediated cardioprotection." American Journal of Physiology-Heart and Circulatory Physiology 301, no. 3 (September 2011): H1183—H1189. http://dx.doi.org/10.1152/ajpheart.00264.2011.
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All four adenosine receptor subtypes have been shown to play a role in cardioprotection, and there is evidence that all four subtypes may be expressed in cardiomyocytes. There is also increasing evidence that optimal adenosine cardioprotection requires the activation of more than one receptor subtype. The purpose of this study was to determine whether adenosine A2A and/or A2B receptors modulate adenosine A1 receptor-mediated cardioprotection. Isolated perfused hearts of wild-type (WT), A2A knockout (KO), and A2BKO mice, perfused at constant pressure and constant heart rate, underwent 30 min of global ischemia and 60 min of reperfusion. The adenosine A1 receptor agonist N6-cyclohexyladenosine (CHA; 200 nM) was administrated 10 min before ischemia and for the first 10 min of reperfusion. Treatment with CHA significantly improved postischemic left ventricular developed pressure (74 ± 4% vs. 44 ± 4% of preischemic left ventricular developed pressure at 60 min of reperfusion) and reduced infarct size (30 ± 2% with CHA vs. 52 ± 5% in control) in WT hearts, effects that were blocked by the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (100 nM). Treatments with the A2A receptor agonist CGS-21680 (200 nM) and the A2B agonist BAY 60-6583 (200 nM) did not exert any beneficial effects. Deletion of adenosine A2A or A2B receptor subtypes did not alter ischemia-reperfusion injury, but CHA failed to exert a cardioprotective effect in hearts of mice from either KO group. These findings indicate that both adenosine A2A and A2B receptors are required for adenosine A1 receptor-mediated cardioprotection, implicating a role for interactions among receptor subtypes.
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Darlington, Daniel N., Xiaowu Wu, Kevin L. Chang, James Bynum, and Andrew P. Cap. "Regulation of Platelet Function By Adenosine Receptors." Blood 134, Supplement_1 (November 13, 2019): 2348. http://dx.doi.org/10.1182/blood-2019-131129.
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Introduction: We have recently shown that severe trauma and hemorrhage lead to inhibition of platelet aggregation and an elevation in cyclic adenosine monophosphate (cAMP). Adenosine is one of the few humoral agents known to stimulate cAMP in platelets. Because adenosine is released from damaged tissue, it may contribute to the platelet dysfunction seen after severe trauma. Platelets have four adenosine receptors (A1, A2a, A2b and A3). These receptors are G-Protein Coupled Receptors and have been proposed to stimulate adenylyl cyclase and increase intracellular cAMP. Although studies have shown that stimulate A2a can inhibit platelet aggregation and elevate cAMP, there is little data elucidating the function of the other receptors. Objective: Define which adenosine receptors affects platelet aggregation and cAMP production. Methods: Platelet-rich plasma (PRP) was isolated from whole blood of human volunteers, and centrifuged at 200g for 10min. Light transmission aggregometry was performed using a plate reader (Synergy Neo2 Multimode Reader, BioTek) with constant agitation. PRP was stimulated with adenosine diphosphate (ADP) with or without various adenosine agonists or antagonists, including the non-metabolizable adenosine agonist 5-(N-ethyl-carboxamido) adenosine (NECA), antagonists to receptors A1 (DPCPX), A2a (Sch 58261), A2b (GS 6201) and A3 (MRS 1220), or agonists for A2a (CGS 21680) A2b (BAY 60-6583) or agonist A1 (CCPA), A2a (CGS 21680), A2b (Bay 60-6583), A3 (2-Cl-IB-Meca). Cyclic AMP was extracted from 100ul of PRP after adding 1ml of EtOH, 10mM ammonium formate, with 10ug/ml cGMP-Br as an internal control. Samples were centrifuged at 20K g for 10min, and supernatant dried. Samples were brought up in 200ul of 0.1% formic acid for analysis by Reverse Phase liquid chromatography/ Tandem Mass Spectroscopy (Quantiva, ThrermoFisher). N-8/group. Results: Adenosine diphosphate (100uM) leads to platelet aggregation (change in mAbsorbance units, Table 1). The adenosine agonist NECA inhibited aggregation to ADP and elevated cAMP in a dose dependent manner (pg/ml per 1000 plt, Table 1). Platelet aggregation was inhibited and cAMP was elevated after stimulation with agonists for adenosine receptor A2a agonist, but not A1, A2b, or A3 (Table 2). Antagonists for A2a, but not A1, A2b, A3, blocked NECA inhibition of ADP aggregation (Table 3). Agonist for adenosine receptor A2a inhibited the ADP-induced aggregation and elevated cAMP in a dose response manner (Table 4). Discussion: Adenosine inhibits platelet aggregation to ADP. The mechanism appears to be due to elevation in intracellular cAMP, and works through the A2a receptor. These data suggest that the A2a receptor could be potential target for a resuscitation strategy that could attenuate or prevent platelet dysfunction after trauma by preventing stimulation of adenylate cyclase and synthesis of cAMP. This study was funded by the US Army medical Research and Development Command. Disclosures No relevant conflicts of interest to declare.
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Marquardt, D. L., L. L. Walker, and S. Heinemann. "Cloning of two adenosine receptor subtypes from mouse bone marrow-derived mast cells." Journal of Immunology 152, no. 9 (May 1, 1994): 4508–15. http://dx.doi.org/10.4049/jimmunol.152.9.4508.
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Abstract Adenosine potentiates the stimulated release of mast cell mediators. Pharmacologic studies suggest the presence of two adenosine receptors, one positively coupled to adenylate cyclase and the other coupled to phospholipase C activation. To identify mast cell adenosine receptor subtypes, cDNAs for the A1 and A2a adenosine receptors were obtained by screening a mouse brain cDNA library with the use of PCR-derived probes. Mouse bone marrow-derived mast cell cDNA libraries were constructed and screened with the use of A1 and A2a cDNA probes, which revealed the presence of A2a, but not A1, receptor clones. A putative A2b receptor was identified by using low stringency mast cell library screening. Northern blotting of mast cell poly(A)+ RNA with the use of receptor subtype probes labeled single mRNA bands of 2.4 kb and 1.8 kb for the A2a and A2b receptors, respectively. In situ cells. An A2a receptor-specific agonist failed to enhance mast cell mediator release, which suggests that the secretory process is modulated through the A2b and/or another receptor subtype. By using RNase protection assays, we found that mast cells that had been cultured in the presence of N-ethylcarboxamidoadenosine for 24 h exhibited a decrease in both A2a and A2b receptor RNA levels. Cells that had been cultured for 1 to 2 days in the presence of dexamethasone demonstrated increased amounts of A2a receptor mRNA, but no identifiable change in A2b receptor mRNA. Mast cells possess at least two adenosine receptor subtypes that may be differentially regulated.
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Rees, D. A., M. D. Lewis, B. M. Lewis, P. J. Smith, M. F. Scanlon, and J. Ham. "Adenosine-Regulated Cell Proliferation in Pituitary Folliculostellate and Endocrine Cells: Differential Roles for the A1 and A2B Adenosine Receptors." Endocrinology 143, no. 6 (June 1, 2002): 2427–36. http://dx.doi.org/10.1210/endo.143.6.8837.
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Abstract A1 and A2 adenosine receptors have been identified in the pituitary gland, but the cell type(s) on which they are located and their effects on pituitary cell growth are not known. Therefore, we analyzed the expression of A1 and A2 receptors in primary rat anterior pituitary cells, two pituitary folliculostellate (TtT/GF and Tpit/F1) and two pituitary endocrine (GH3 and AtT20) cell lines, and compared their effects on cell proliferation. In anterior pituitary and folliculostellate cells, adenosine and adenosine receptor agonists (5′-N-ethylcarboxamidoadenosine, a universal agonist, and CGS 21680, an A2A receptor agonist) stimulated cAMP levels with a rank order of potency that indicates the presence of functional A2B receptors. This stimulation, however, was not observed in either GH3 or AtT20 cells, where adenosine and the A1 receptor agonist 2-chloro-N6-cyclopentyladenosine inhibited VIP/forskolin-stimulated cAMP production. Expression of A2B and A1 receptors in the folliculostellate cells and that of the A1 receptor in the endocrine cells were confirmed by RT-PCR, immunocytochemistry, and ligand binding. Adenosine and 5′-N-ethylcarboxamidoadenosine dose-dependently (10 nm to 10 μm) stimulated growth in the folliculostellate, but not in the endocrine, cells, whereas in the latter, 100 μm adenosine and 2-chloro-N6-cyclopentyladenosine inhibited cell proliferation by slowing cell cycle progression. These data highlight the differential expression of A1 and A2B adenosine receptors in pituitary cells and provide evidence for opposing effects of adenosine on pituitary folliculostellate and endocrine cell growth.
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Kreisberg, M. S., E. P. Silldorff, and T. L. Pallone. "Localization of adenosine-receptor subtype mRNA in rat outer medullary descending vasa recta by RT-PCR." American Journal of Physiology-Heart and Circulatory Physiology 272, no. 3 (March 1, 1997): H1231—H1238. http://dx.doi.org/10.1152/ajpheart.1997.272.3.h1231.
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Adenosine has a multitude of functions in the kidney, including vasoregulation of the renal vasculature. The actions of adenosine are mediated by its binding to specific receptors. Four adenosine-receptor subtypes have been cloned and sequenced, the A1, A2a, A2b, and the A3. In this study, the expression of individual adenosine-receptor subtype RNAs in outer medullary descending vasa recta (OMDVR) was investigated. Total RNA isolated from the outer medulla and microdissected, permeabilized OMDVR were subjected to reverse transcription-polymerase chain reaction (RT-PCR) with primers specific for each of the adenosine-receptor subtypes. Subtype-specific probes were used to verify the PCR products by Southern hybridization. Our studies, performed in triplicate on five different rats, indicate the presence of A1, A2a, and A2b adenosine-receptor subtype mRNAs. These products were not attributable to extraneous RNA contamination from other tissue sources, nor did they result from genomic DNA amplification. These data are consistent with pharmacological evaluations, favor A1, A2a, and A2b adenosine-receptor subtype expression in OMDVR, and support a role for adenosine in the regulation of medullary blood flow.
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Gebremedhin, Debebe, Brian Weinberger, David Lourim, and David R. Harder. "Adenosine Can Mediate its Actions through Generation of Reactive Oxygen Species." Journal of Cerebral Blood Flow & Metabolism 30, no. 10 (June 9, 2010): 1777–90. http://dx.doi.org/10.1038/jcbfm.2010.70.
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Adenosine is an important cerebral vasodilator, but mediating mechanisms are not understood. We investigated the expression of adenosine receptor subtypes in isolated cerebral arterial muscle cells (CAMCs), and their role in adenosine-induced superoxide (O2−) generation and reduction in cerebral arterial tone. Reverse transcriptase-PCR, western blotting, and immunofluorescence studies have shown that CAMCs express transcript and protein for A1, A2A, A2B, and A3 adenosine receptors. Stimulation of CAMCs with adenosine or the A2A agonist CGS-21680 increased the generation of O2− that was attenuated by the inhibition of A2A and A2B adenosine receptor subtypes, or by the peptide inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase gp91ds-tat, or by the mitochondria uncoupler 2,4-dinitrophenol. Application of adenosine or CGS-21680 dilated pressure-constricted cerebral arterial segments that were prevented by the antioxidants superoxide dismutase (SOD) conjugated to polyethylene glycol (PEG) and PEG-catalase or by the A2B adenosine receptor antagonist MRS-1754, or by the mixed A2A and A2B antagonist ZM-241385. Antagonism of the A2A and A2B adenosine receptors had no effect on cerebral vasodilatation induced by nifedipine. These findings indicate that adenosine reduces pressure-induced cerebral arterial tone through stimulation of A2A and A2B adenosine receptors and generation of O2− from NADPH oxidase and mitochondrial sources. This signaling pathway could be one of the mediators of the cerebral vasodilatory actions of adenosine.
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Allen-Gipson, Diane S., Michael R. Blackburn, Daniel J. Schneider, Hui Zhang, DeAndre L. Bluitt, Justin C. Jarrell, Daniel Yanov, Joseph H. Sisson, and Todd A. Wyatt. "Adenosine activation of A2B receptor(s) is essential for stimulated epithelial ciliary motility and clearance." American Journal of Physiology-Lung Cellular and Molecular Physiology 301, no. 2 (August 2011): L171—L180. http://dx.doi.org/10.1152/ajplung.00203.2010.
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Mucociliary clearance, vital to lung clearance, is dependent on cilia beat frequency (CBF), coordination of cilia, and the maintenance of periciliary fluid. Adenosine, the metabolic breakdown product of ATP, is an important modulator of ciliary motility. However, the contributions of specific adenosine receptors to key airway ciliary motility processes are unclear. We hypothesized that adenosine modulates ciliary motility via activation of its cell surface receptors (A1, A2A, A2B, or A3). To test this hypothesis, mouse tracheal rings (MTRs) excised from wild-type and adenosine receptor knockout mice (A1, A2A, A2B, or A3, respectively), and bovine ciliated bronchial epithelial cells (BBECs) were stimulated with known cilia activators, isoproterenol (ISO; 10 μM) and/or procaterol (10 μM), in the presence or absence of 5′-(N-ethylcarboxamido) adenosine (NECA), a nonselective adenosine receptor agonist [100 nM (A1, A2A, A3); 10 μM (A2B)], and CBF was measured. Cells and MTRs were also stimulated with NECA (100 nM or 10 μM) in the presence and absence of adenosine deaminase inhibitor, erythro-9- (2-hydroxy-3-nonyl) adenine hydrochloride (10 μM). Both ISO and procaterol stimulated CBF in untreated cells and/or MTRs from both wild-type and adenosine knockout mice by ∼3 Hz. Likewise, CBF significantly increased ∼2–3 Hz in BBECs and wild-type MTRs stimulated with NECA. MTRs from A1, A2A, and A3 knockout mice stimulated with NECA also demonstrated an increase in CBF. However, NECA failed to stimulate CBF in MTRs from A2B knockout mice. To confirm the mechanism by which adenosine modulates CBF, protein kinase activity assays were conducted. The data revealed that NECA-stimulated CBF is mediated by the activation of cAMP-dependent PKA. Collectively, these data indicate that purinergic stimulation of CBF requires A2B adenosine receptor activation, likely via a PKA-dependent pathway.
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Garcia-Garcia, Lucia, Laia Olle, Margarita Martin, Jordi Roca-Ferrer, and Rosa Muñoz-Cano. "Adenosine Signaling in Mast Cells and Allergic Diseases." International Journal of Molecular Sciences 22, no. 10 (May 14, 2021): 5203. http://dx.doi.org/10.3390/ijms22105203.
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Adenosine is a nucleoside involved in the pathogenesis of allergic diseases. Its effects are mediated through its binding to G protein-coupled receptors: A1, A2a, A2b and A3. The receptors differ in the type of G protein they recruit, in the effect on adenylyl cyclase (AC) activity and the downstream signaling pathway triggered. Adenosine can produce both an enhancement and an inhibition of mast cell degranulation, indicating that adenosine effects on these receptors is controversial and remains to be clarified. Depending on the study model, A1, A2b, and A3 receptors have shown anti- or pro-inflammatory activity. However, most studies reported an anti-inflammatory activity of A2a receptor. The precise knowledge of the adenosine mechanism of action may allow to develop more efficient therapies for allergic diseases by using selective agonist and antagonist against specific receptor subtypes.
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Xaus, Jordi, Maribel Mirabet, Jorge Lloberas, Concepció Soler, Carme Lluis, Rafael Franco, and Antonio Celada. "IFN-γ Up-Regulates the A2B Adenosine Receptor Expression in Macrophages: A Mechanism of Macrophage Deactivation." Journal of Immunology 162, no. 6 (March 15, 1999): 3607–14. http://dx.doi.org/10.4049/jimmunol.162.6.3607.
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Abstract Adenosine is a potent endogenous anti-inflammatory agent released by cells in metabolically unfavorable conditions, such as hypoxia or ischemia. Adenosine modulates different functional activities in macrophages. Some of these activities are believed to be induced through the uptake of adenosine into the macrophages, while others are due to the interaction with specific cell surface receptors. In murine bone marrow-derived macrophages, the use of different radioligands for adenosine receptors suggests the presence of A2B and A3 adenosine receptor subtypes. The presence of A2B receptors was confirmed by flow cytometry using specific Abs. The A2B receptor is functional in murine macrophages, as indicated by the fact that agonists of A2B receptors, but not agonists for A1, A2A, or A3, lead to an increase in cAMP levels. IFN-γ up-regulates the surface protein and gene expression of the A2B adenosine receptor by induction of de novo synthesis. The up-regulation of A2B receptors correlates with an increase in cAMP production in macrophages treated with adenosine receptor agonist. The stimulation of A2B receptors by adenosine or its analogues inhibits the IFN-γ-induced expression of MHC class II genes and also the IFN-γ-induced expression of nitric oxide synthase and of proinflammatory cytokines. Therefore, the up-regulation of the A2B adenosine receptor expression induced by IFN-γ could be a feedback mechanism for macrophage deactivation.
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Teng, Bunyan, Daniel N. Darlington, and Andrew P. Cap. "Adenosine Receptor Identification for Controlling Platelet Aggregation." Blood 132, Supplement 1 (November 29, 2018): 3733. http://dx.doi.org/10.1182/blood-2018-99-116213.
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Abstract Introduction: Adenosine, an autacoid and metabolite of ATP, has been known to have anti-platelet properties. Of the 4 adenosine receptors, both A2A and/or A2B have been implicated in adenosine-mediated anti-platelet properties, while the roles of A1 and A3 have not been clearly defined in humans. In addition, previous studies show that A2A/A2B on platelets are G-Protein Coupled Receptors and are coupled to a stimulatory G-protein that activate adenylyl cyclase and subsequently increase intracellular cAMP. An elevation of cAMP in platelets inhibits aggregation. In this study, we set out to determine which adenosine receptor subtype leads to inhibition of platelet aggregation, and change in intracellular cAMP. Materials and Methods: Platelet-rich plasma (PRP) was isolated from whole blood of human volunteers, and centrifuged at 200g for 10min. Light transmission aggregometry was performed by 100uM ADP with or without NECA (non-specific AR agonist), CCPA (A1 AR agonist), CGS 21680 (A2A AR agonist), BAY 60-6583 (A2B AR agonist), DPCPX (A1 AR antagonist), Sch 58261 (A2A AR antagonist), GS 6201 (A2B AR antagonist), and MRS 1220 (A3 AR antagonist). Cyclic AMP was extracted from 100ul of PRP after adding 1ml of EtOH, 10mM ammonium formate, with 10ug/ml cGMP-Br as an internal control, and measured by liquid chromatography/ Tandem Mass Spectroscopy (Quantiva, ThrermoFisher). Results: ADP-induced platelet aggregation was inhibited in a dose dependent manner by the non-specific adenosine agonist, NECA (Figure 1). This inhibition of platelet aggregation was likely mediated by A2A receptor as the specific A2A receptor agonist had a similar effect (Figure 2). Furthermore, A2A antagonist blocked the effects of NECA (Figure 5). Stimulation of A1 receptor had no effect on the ADP-induced platelet aggregation, except at the highest concentration (250 µM), and is likely due to its non-specific effect on A2A AR (Figures 3 and 4). Blockade of A1 enhanced the effects of NECA (Figure 5). This suggest that A2A and A1 may have opposing roles for control of platelet aggregation. Stimulation of A2B receptor, had no effect on ADP-induced platelet aggregation, except at the highest concentration (250 µM), which was likely due to the non-specific vehicle effects (2.5% DMSO, Figure 6). Blockade of A2B receptor had no effect on NECA, while A3 blockade showed slight inhibition on NECA's anti-platelet effect (data not shown). NECA inhibition of platelet aggregation was likely due to elevation of intracellular cAMP as incubation for 5min with NECA stimulated intracellular cAMP (Figure 7). This effect was blocked by A2A, not by A1 antagonist. Conclusion: Our results support previous findings that adenosine receptor A2A mediates adenosine-induced anti-platelet properties in human platelets. Adenosine and its analogs inhibit platelet aggregation to the natural stimulus, ADP. The mechanism appears to be due to elevation in intracellular cAMP. We did not find evidence that A2B played a significant role in platelet aggregation. A1 and A3. however, demonstrated modulatory effects that has not been previously described. Disclosures No relevant conflicts of interest to declare.
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Zaynagetdinov, Rinat, Kai Schiemann, Kalyan Nallaparaju, Natalya Belousova, Armine Matevossian, Zhouxiang Chen, Giorgio Kradjian, et al. "Abstract 3499: M1069 as dual A2A/A2B adenosine receptor antagonist counteracts immune-suppressive mechanisms of adenosine and reduces tumor growth in vivo." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3499. http://dx.doi.org/10.1158/1538-7445.am2022-3499.
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Abstract Under physiological conditions, the extracellular concentrations of adenosine are low, however, levels dramatically increase under metabolically stressful conditions, including inflammation and cancer. The regulatory functions of adenosine are mediated through four members of the adenosine receptor family: A1, A2A, A2B, and A3. While A2A was considered the major contributor to adenosine-mediated suppression of T cell, natural killer cell, and myeloid cell functions, A2B has also recently emerged as a potential modulator of these processes. Both A2A and A2B signal through the same Gs-mediated activation of adenylate cyclase, which can allow the lower affinity A2B receptor to compensate for the inhibition of A2A in an adenosine-rich tumor microenvironment (TME). A2B receptors are also reported to support tumor growth independent of A2A through the Gq subunit of G-protein-coupled receptor-mediated production of vascular endothelial growth factor (VEGF) by myeloid and tumor cells. Therefore, simultaneous targeting of both the A2A and A2B receptors may provide a higher potential for cancer immunotherapy in an adenosine-rich TME, where A2B can act in compensatory or complementary means to A2A. M1069 is a small-molecule, dual antagonist of the A2A and A2B adenosine receptors with a selectivity of >100 fold against the A1 and A3 receptors. In assays with primary human T cells, M1069 caused a dose-dependent suppression of 5′-N-ethylcarboxamide adenosine (stable analog of adenosine)-stimulated cyclic adenosine monophosphate (cAMP) and phosphorylated cAMP- response element binding protein (pCREB) induction and rescue of interleukin (IL)-2 production (A2A readout). M1069 also suppressed VEGF production from human macrophages (A2B readout) in adenosine-rich settings. M1069 exhibited superior suppression of protumorigenic cytokine secretion, including CXCL1, CXCL5 and granulocyte-colony stimulating factor, and the rescue of IL12 secretion from adenosine-differentiated dendritic cells, as compared to an A2Aselective antagonist. In addition, in a one-way mixed lymphocyte reaction assay, adenosine-differentiated dendritic cells treated with M1069 demonstrated superior T cell activation compared to adenosine-differentiated dendritic cells treated with an A2A-selective antagonist. These findings were further corroborated with the results from in vivo studies in a murine CD73hi/adenosine-rich 4T1 syngeneic breast tumor model, in which M1069, but not an A2A-selective antagonist, reduced tumor growth as a monotherapy and enhanced anti-tumor activity with chemotherapeutic agents. In summary, M1069 is a potent, dual A2A/A2B adenosine receptor antagonist, which is expected to counteract immune-suppressive mechanisms in the presence of high concentrations of adenosine and enhance the anti-tumor activity of chemotherapies. Citation Format: Rinat Zaynagetdinov, Kai Schiemann, Kalyan Nallaparaju, Natalya Belousova, Armine Matevossian, Zhouxiang Chen, Giorgio Kradjian, Meghana Pandya, Nemisha Dawra, Eva-Maria Krauel, Elissaveta Petrova, Oliver Poeschke, David Fischer, Marc Lecomte, Andree Blaukat, Bayard Huck, Jacques Moisan. M1069 as dual A2A/A2B adenosine receptor antagonist counteracts immune-suppressive mechanisms of adenosine and reduces tumor growth in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3499.
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Jackson, Edwin K., Chongxue Zhu, and Stevan P. Tofovic. "Expression of adenosine receptors in the preglomerular microcirculation." American Journal of Physiology-Renal Physiology 283, no. 1 (July 1, 2002): F41—F51. http://dx.doi.org/10.1152/ajprenal.00232.2001.
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The purpose of this study was to systematically investigate the abundance of each of the adenosine receptor subtypes in the preglomerular microcirculation vs. other vascular segments and vs. the renal cortex and medulla. Rat preglomerular microvessels (PGMVs) were isolated by iron oxide loading followed by magnetic separation. For comparison, mesenteric microvessels, segments of the aorta (thoracic, middle abdominal, and lower abdominal), renal cortex, and renal medulla were obtained by dissection. Adenosine receptor protein and mRNA expression were examined by Western blotting, Northern blotting, and RT-PCR. Our results indicate that compared with other vascular segments and renal tissues, A1 and A2B receptor protein and mRNA are abundantly expressed in the preglomerular microcirculation, whereas A2A and A3 receptor protein and mRNA are barely detectable or undetectable in PGMVs. We conclude that, relative to other vascular and renal tissues, A1 and A2Breceptors are well expressed in PGMVs, whereas A2A and A3 receptors are notably deficient. Thus A1 and A2B receptors, but not A2A or A3receptors, may importantly regulate the preglomerular microcirculation.
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Lu, Yan, Rui Zhang, Ying Ge, Mattias Carlstrom, Shaohui Wang, Yiling Fu, Liang Cheng, et al. "Identification and function of adenosine A3 receptor in afferent arterioles." American Journal of Physiology-Renal Physiology 308, no. 9 (May 1, 2015): F1020—F1025. http://dx.doi.org/10.1152/ajprenal.00422.2014.
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Adenosine plays an important role in regulation of renal microcirculation. All receptors of adenosine, A1, A2A, A2B, and A3, have been found in the kidney. However, little is known about the location and function of the A3 receptor in the kidney. The present study determined the expression and role of A3 receptors in mediating the afferent arteriole (Af-Art) response and studied the interaction of A3 receptors with angiotensin II (ANG II), A1 and A2 receptors on the Af-Art. We found that the A3 receptor expressed in microdissected isolated Af-Art and the mRNA levels of A3 receptor were 59% of A1. In the isolated microperfused Af-Art, A3 receptor agonist IB-MECA did not have a constrictive effect. Activation of A3 receptor dilated the preconstricted Af-Art by norepinephrine and blunted the vasoconstrictive effect of both adenosine A1 receptor activation and ANG II on the Af-Art, respectively. Selective A2 receptor antagonist (both A2A and A2B) had no effect on A3 receptor agonist-induced vasodilation, indicating that the dilatory effect of A3 receptor activation is not mediated by activation of A2 receptor. We conclude that the A3 receptor is expressed in the Af-Art, and activation of the A3 receptor dilates the Af-Art.
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Fan, Ming, Weixi Qin, and S. Jamal Mustafa. "Characterization of adenosine receptor(s) involved in adenosine-induced bronchoconstriction in an allergic mouse model." American Journal of Physiology-Lung Cellular and Molecular Physiology 284, no. 6 (June 1, 2003): L1012—L1019. http://dx.doi.org/10.1152/ajplung.00353.2002.
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We recently reported that adenosine caused bronchoconstriction and enhanced airway inflammation in an allergic mouse model. In this study, we further report the characterization of the subtype of adenosine receptor(s) involved in bronchoconstriction. 5′-( N-ethylcarboxamido)adenosine (NECA), a nonselective adenosine agonist, elicited bronchoconstriction in a dose-dependent manner. Little effects of N 6-cyclopentyladenosine (A1-selective agonist) and 2- p-(2-carboxyethyl)phenethylamino-5′- N-ethylcarboxamidoadenosine (A2A-selective agonist) compared with NECA were observed in this model. 2-Chloro- N 6-(3-iodobenzyl)-9-[5-(methylcarbamoyl)-β-d-ribofuranosyl]adenosine, an A3-selective receptor agonist, produced a dose-dependent bronchoconstrictor response, which was blocked by selective A3 antagonist 2,3-diethyl-4,5-dipropyl-6-phenylpyridine-3-thiocarboxylate-5-carboxylate (MRS1523). However, MRS1523 only partially inhibited NECA-induced bronchoconstriction. Neither selective A1 nor A2A antagonists affected NECA-induced bronchoconstriction. Enprofylline, a relatively selective A2B receptor antagonist, blocked partly NECA-induced bronchoconstriction. Furthermore, a combination of enprofylline and MRS1523 completely abolished NECA-induced bronchoconstrictor response. Using RT-PCR, we found that all four adenosine receptor subtypes are expressed in control lungs. Allergen sensitization and challenge significantly increased transcript levels of the A2B and A3receptors, whereas the A1 receptor message decreased. No change in transcript levels of A2A receptors was observed after allergen sensitization and challenge. These findings suggest that A2B and A3 adenosine receptors play an important role in adenosine-induced bronchoconstriction in our allergic mouse model. Finally, whether the airway effects of the receptor agonists/antagonists are direct or indirect needs further investigations.
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Yu, Weiqun, Lefteris C. Zacharia, Edwin K. Jackson, and Gerard Apodaca. "Adenosine receptor expression and function in bladder uroepithelium." American Journal of Physiology-Cell Physiology 291, no. 2 (August 2006): C254—C265. http://dx.doi.org/10.1152/ajpcell.00025.2006.
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The uroepithelium of the bladder forms an impermeable barrier that is maintained in part by regulated membrane turnover in the outermost umbrella cell layer. Other than bladder filling, few physiological regulators of this process are known. Western blot analysis established that all four adenosine receptors (A1, A2a, A2b, and A3) are expressed in the uroepithelium. A1 receptors were prominently localized to the apical membrane of the umbrella cell layer, whereas A2a, A2b, and A3 receptors were localized intracellularly or on the basolateral membrane of umbrella cells and the plasma membrane of the underlying cell layers. Adenosine was released from the uroepithelium, which was potentiated 10-fold by stretching the tissue. Administration of adenosine to the serosal or mucosal surface of the uroepithelium led to increases in membrane capacitance (where 1 μF ≈ 1 cm2 tissue area) of ∼30% or ∼24%, respectively, after 5 h. Although A1, A2a, and A3 selective agonists all stimulated membrane capacitance after being administrated serosally, only the A1 agonist caused large increases in capacitance after being administered mucosally. Adenosine receptor antagonists as well as adenosine deaminase had no effect on stretch-induced capacitance increases, but adenosine potentiated the effects of stretch. Treatment with U-73122, 2-aminoethoxydiphenylborate, or xestospongin C or incubation in calcium-free Krebs solution inhibited adenosine-induced increases in capacitance. These data indicate that the uroepithelium is a site of adenosine biosynthesis, that adenosine receptors are expressed in the uroepithelium, and that one function of these receptors may be to modulate exocytosis in umbrella cells.
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Lu, Qing, Elizabeth O. Harrington, Julie Newton, Brian Casserly, Gregory Radin, Rod Warburton, Yang Zhou, Michael R. Blackburn, and Sharon Rounds. "Adenosine protected against pulmonary edema through transporter- and receptor A2-mediated endothelial barrier enhancement." American Journal of Physiology-Lung Cellular and Molecular Physiology 298, no. 6 (June 2010): L755—L767. http://dx.doi.org/10.1152/ajplung.00330.2009.
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We have previously demonstrated that adenosine plus homocysteine enhanced endothelial basal barrier function and protected against agonist-induced barrier dysfunction in vitro through attenuation of RhoA activation by inhibition of isoprenylcysteine-O-carboxyl methyltransferase. In the current study, we tested the effect of elevated adenosine on pulmonary endothelial barrier function in vitro and in vivo. We noted that adenosine alone dose dependently enhanced endothelial barrier function. While adenosine receptor A1 or A3 antagonists were ineffective, an adenosine transporter inhibitor, NBTI, or a combination of DPMX and MRS1754, antagonists for adenosine receptors A2A and A2B, respectively, partially attenuated the barrier-enhancing effect of adenosine. Similarly, inhibition of both A2A and A2B receptors with siRNA also blunted the effect of adenosine on barrier function. Interestingly, inhibition of both transporters and A2A/A2B receptors completely abolished adenosine-induced endothelial barrier enhancement. The adenosine receptor A2A and A2B agonist, NECA, also significantly enhanced endothelial barrier function. These data suggest that both adenosine transporters and A2A and A2B receptors are necessary for exerting maximal effect of adenosine on barrier enhancement. We also found that adenosine enhanced Rac1 GTPase activity and overexpression of dominant negative Rac1 attenuated adenosine-induced increases in focal adhesion complexes. We further demonstrated that elevation of cellular adenosine by inhibition of adenosine deaminase with Pentostatin significantly enhanced endothelial basal barrier function, an effect that was also associated with enhanced Rac1 GTPase activity and with increased focal adhesion complexes and adherens junctions. Finally, using a non-inflammatory acute lung injury (ALI) model induced by α-naphthylthiourea, we found that administration of Pentostatin, which elevated lung adenosine level by 10-fold, not only attenuated the development of edema before ALI but also partially reversed edema after ALI. The data suggest that adenosine deaminase inhibition may be useful in treatment of pulmonary edema in settings of ALI.
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Maille, Baptiste, Nathalie Lalevée, Marion Marlinge, Juliette Vahdat, Giovanna Mottola, Clara Degioanni, Lucille De Maria, et al. "Adenosine and Adenosine Receptors: Advances in Atrial Fibrillation." Biomedicines 10, no. 11 (November 17, 2022): 2963. http://dx.doi.org/10.3390/biomedicines10112963.
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Atrial fibrillation (AF) is the most common arrhythmia in the world. Because the key to developing innovative therapies that limit the onset and the progression of AF is to fully understand the underlying molecular mechanisms of AF, the aim of the present narrative review is to report the most recent advances in the potential role of the adenosinergic system in the pathophysiology of AF. After a comprehensive approach describing adenosinergic system signaling and the mechanisms of the initiation and maintenance of AF, we address the interactions of the adenosinergic system’s signaling with AF. Indeed, adenosine release can activate four G-coupled membrane receptors, named A1, A2A, A2B and A3. Activation of the A2A receptors can promote the occurrence of delayed depolarization, while activation of the A1 receptors can shorten the action potential’s duration and induce the resting membrane’s potential hyperpolarization, which promote pulmonary vein firing, stabilize the AF rotors and allow for functional reentry. Moreover, the A2B receptors have been associated with atrial fibrosis homeostasis. Finally, the adenosinergic system can modulate the autonomous nervous system and is associated with AF risk factors. A question remains regarding adenosine release and the adenosine receptors’ activation and whether this would be a cause or consequence of AF.
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Baraldi, P. G., B. Cacciar, G. Spalluto, A. Borioni, M. Viziano, S. Dionisotti, and E. Ongini. "Current Developments of A2a Adenosine Receptor Antagonists." Current Medicinal Chemistry 2, no. 3 (October 1995): 707–22. http://dx.doi.org/10.2174/092986730203220223144628.
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<P>Adenosine regulates a wide range of physiological functions through specific cell membrane receptors. On the basis of pharmacological studies and molecular cloning, four distinct adenosine receptors have been identified and classified as A1, A2a. A2b and A3. These adenosine receptors are members of the G-protein-coupled receptor family. <P> An intense medicinal chemistry effort made over the last 20 years has led to a variety of selective adenosine receptor agonists and antagonists. While all the agonists thus far identified are related to the adenosine structure, the antagonists available belong to different chemical classes. The prototypic antagonists are xanthine derivatives evolved from the natural compounds, caffeine and theophylline. Typically, they are 8-substituted-1,2,3-trialkylxanthine and are A1 selective antagonists. More recently, 8-styrylxanthines have been found to be selective for A2a receptors. Other non-xanthine heterocycles are potent A2a antagonists and possess different degree of selectivity. Selective antagonists are not available yet for A2b and A3 receptors. <P> Given the recent developments of A2a selective antagonists, we have reviewed their chemical structures and biological properties in the attempts to get insight into this emerging class of new interesting compounds. The development of some of the A2a antagonists will provide better understanding of the role of A2a receptors in physiological and pathological states. The compounds appear also to have the potential to be useful for the treatment of cerebral ischemia or neurodegenerative disorders, such as Parkinson's disease.</P>
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Franco, Rafael, Rafael Rivas-Santisteban, Gemma Navarro, and Irene Reyes-Resina. "Adenosine Receptor Antagonists to Combat Cancer and to Boost Anti-Cancer Chemotherapy and Immunotherapy." Cells 10, no. 11 (October 21, 2021): 2831. http://dx.doi.org/10.3390/cells10112831.
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Extracellular adenosine accumulates in the environment of numerous tumors. For years, this fact has fueled preclinical research to determine whether adenosine receptors (ARs) could be the target to fight cancer. The four ARs discovered so far, A1, A2A, A2B and A3, belong to the class A family of G protein-coupled receptors (GPCRs) and all four have been involved in one way or another in regulating tumor progression. Prompted by the successful anti-cancer immunotherapy, the focus was placed on the ARs more involved in regulation of immune cell differentiation and activation and that are able to establish molecular and functional interactions. This review focuses on the potential of A2A and A2B receptor antagonists in cancer control and in boosting anti-cancer chemotherapy and immunotherapy. The article also overviews the ongoing clinical trials in which A2AR and A2BR ligands are being tested in anti-cancer therapy.
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Hassanian, Seyed Mahdi, and Alireza R. Rezaie. "Adenosine Inhibits Pro-Inflammatory Thrombin Signaling In Endothelial Cells." Blood 122, no. 21 (November 15, 2013): 1064. http://dx.doi.org/10.1182/blood.v122.21.1064.1064.
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Abstract Adenosine is an important regulatory metabolite which attenuates inflammation when it binds and activates the adenosine A2A receptor subtype on immune cells. However, the effect of adenosine on inflammatory responses in endothelial cells is mostly unknown. Thrombin as a known pro-inflammatory protease is involved in a variety of pathophysiological processes associated with inflammation in stimulated endothelial cells. The present study investigated the effect of adenosine on thrombin-mediated modulation of pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs). Adenosine, in a concentration-dependent manner (1-100µM), inhibited the barrier disruptive effect of thrombin (20nM) on endothelial monolayer. The expression level of adenosine receptors, A1, A2A, A2B and A3 was examined in HUVECs and it was found that A2A and A2B are the highest expressing receptors among the four subtypes (A2B> A2A>A1>A3) in endothelial cells. Further studies revealed that the barrier protective effect of adenosine on thrombin-induced hyperpermeability in HUVECs was abrogated by the A2A receptor specific siRNA or the A2A receptor specific antagonist, ZM-241385, but not by siRNAs targeting the other adenosine receptor subtypes. To further determine the molecular mechanisms of the barrier protective effect of adenosine, its effect on thrombin-induced RhoA activation was assessed. Pretreatment of endothelial cells with adenosine prevented both thrombin-induced RhoA activation (Rho-GTP) and its membrane translocation as evidenced by cell fractionation and Pull-down assays, respectively. Moreover, preincubation of endothelial cells with adenosine down-regulated the expression of cell surface adhesion molecules (VCAM-1 and ICAM-1) and thrombin-mediated activation of nuclear factor-kappaB (NF-kB) pathway. Adenosine also inhibited secretion of the early chemokine, MCP-1, and the late-acting pro-inflammatory cytokine, HMGB-1, by thrombin-stimulated endothelial cells. Taken together, these results suggest that adenosine can inhibit pro-inflammatory thrombin signaling responses in endothelial cells by specifically activating the A2A receptor subtype, thereby protecting endothelium during the activation of coagulation and inflammatory pathways. Disclosures: No relevant conflicts of interest to declare.
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Arin, Rosa María, Ana Isabel Vallejo, Yuri Rueda, Olatz Fresnedo, and Begoña Ochoa. "Stimulation of gastric acid secretion by rabbit parietal cell A2B adenosine receptor activation." American Journal of Physiology-Cell Physiology 309, no. 12 (December 15, 2015): C823—C834. http://dx.doi.org/10.1152/ajpcell.00224.2015.
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Adenosine modulates different functional activities in many cells of the gastrointestinal tract; some of them are believed to be mediated by interaction with its four G protein-coupled receptors. The renewed interest in the adenosine A2B receptor (A2BR) subtype can be traced by studies in which the introduction of new genetic and chemical tools has widened the pharmacological and structural knowledge of this receptor as well as its potential therapeutic use in cancer and inflammation- or hypoxia-related pathologies. In the acid-secreting parietal cells of the gastric mucosa, the use of various radioligands for adenosine receptors suggested the presence of the A2 adenosine receptor subtype(s) on the cell surface. Recently, we confirmed A2BR expression in native, nontransformed parietal cells at rest by using flow cytometry and confocal microscopy. In this study, we show that A2BR is functional in primary rabbit gastric parietal cells, as indicated by the fact that agonist binding to A2BR increased adenylate cyclase activity and acid production. In addition, both acid production and radioligand binding of adenosine analogs to isolated cell membranes were potently blocked by selective A2BR antagonists, whereas ligands for A1, A2A, and A3 adenosine receptors failed to abolish activation. We conclude that rabbit gastric parietal cells possess functional A2BR proteins that are coupled to Gs and stimulate HCl production upon activation. Whether adenosine- and A2BR-mediated functional responses play a role in human gastric pathophysiology is yet to be elucidated.
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Cao, Wei, Yanggang Yuan, Xi Liu, Qing Li, Xiaofei An, Zhimin Huang, Lin Wu, Bo Zhang, Aihua Zhang, and Changying Xing. "Adenosine kinase inhibition protects against cisplatin-induced nephrotoxicity." American Journal of Physiology-Renal Physiology 317, no. 1 (July 1, 2019): F107—F115. http://dx.doi.org/10.1152/ajprenal.00385.2018.
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Numerous studies have demonstrated that several mechanisms, including oxidative stress, DNA damage, and inflammatory responses, are closely linked to cisplatin-induced nephrotoxicity. Adenosine, emerging as a key regulatory molecule, is mostly protective in the pathophysiology of inflammatory diseases. A previous study showed that some of the adenosine receptors led to renal protection against ischemia-reperfusion injury. However, these adenosine receptor agonists lack a useful therapeutic index due to cardiovascular side effects. We hypothesized that inhibition of adenosine kinase (ADK) might exacerbate extracellular adenosine levels to reduce cisplatin-induced renal injury. In the present study, pretreatment with the ADK inhibitor ABT-702 could markedly attenuate cisplatin-induced acute kidney injury, tubular cell apoptosis, oxidative stress, and inflammation in the kidneys. Consistent with in vivo results, inhibition of ADK suppressed cisplatin-induced apoptosis, reactive oxygen species production, and inflammation in HK2 cells. Additionally, the protective effect of ADK inhibition was abolished by A1 or A2B adenosine receptor antagonist and enhanced by A2A or A3 adenosine receptor antagonist. Collectively, the results suggest that inhibition of ADK might increase extracellular adenosine levels, which inhibited cisplatin-induced oxidative stress and inflammation via A1 and A2B adenosine receptors, finally suppressing cisplatin-induced cell apoptosis. Pharmacological therapies based on ADK will be of potential use in therapy of cisplatin-induced nephrotoxicity.
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Kotańska, Magdalena, Anna Dziubina, Małgorzata Szafarz, Kamil Mika, Marek Bednarski, Noemi Nicosia, Ahmed Temirak, Christa E. Müller, and Katarzyna Kieć-Kononowicz. "Preliminary Evidence of the Potent and Selective Adenosine A2B Receptor Antagonist PSB-603 in Reducing Obesity and Some of Its Associated Metabolic Disorders in Mice." International Journal of Molecular Sciences 23, no. 21 (November 3, 2022): 13439. http://dx.doi.org/10.3390/ijms232113439.
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The adenosine A2A and A2B receptors are promising therapeutic targets in the treatment of obesity and diabetes since the agonists and antagonists of these receptors have the potential to positively affect metabolic disorders. The present study investigated the link between body weight reduction, glucose homeostasis, and anti-inflammatory activity induced by a highly potent and specific adenosine A2B receptor antagonist, compound PSB-603. Mice were fed a high-fat diet for 14 weeks, and after 12 weeks, they were treated for 14 days intraperitoneally with the test compound. The A1/A2A/A2B receptor antagonist theophylline was used as a reference. Following two weeks of treatment, different biochemical parameters were determined, including total cholesterol, triglycerides, glucose, TNF-α, and IL-6 blood levels, as well as glucose and insulin tolerance. To avoid false positive results, mouse locomotor and spontaneous activities were assessed. Both theophylline and PSB-603 significantly reduced body weight in obese mice. Both compounds had no effects on glucose levels in the obese state; however, PSB-603, contrary to theophylline, significantly reduced triglycerides and total cholesterol blood levels. Thus, our observations showed that selective A2B adenosine receptor blockade has a more favourable effect on the lipid profile than nonselective inhibition.
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Allen-Gipson, D. S., J. Wong, J. R. Spurzem, J. H. Sisson, and T. A. Wyatt. "Adenosine A2A receptors promote adenosine-stimulated wound healing in bronchial epithelial cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 290, no. 5 (May 2006): L849—L855. http://dx.doi.org/10.1152/ajplung.00373.2005.
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Adenosine produces a wide variety of physiological effects through the activation of specific adenosine receptors (A1, A2A, A2B, A3). Adenosine, acting particularly at the A2A adenosine receptor (A2AAR), is a potent endogenous anti-inflammatory agent and sensor of inflammatory tissue damage. The complete healing of wounds is the final step in a highly regulated response to injury. Recent studies on epidermal wounds have identified the A2AAR as the main adenosine receptor responsible for altering the kinetics of wound closure. We hypothesized that A2AAR promotes wound healing in bronchial epithelial cells (BECs). To test this hypothesis, the human BEC line BEAS-2B and bovine BECs (BBECs) were used. Real-time RT-PCR of RNA from unstimulated BEAS-2B cells revealed transcriptional expression of A1, A2A, A2B and A3 receptors. Western blot analysis of lysates from BEAS-2B cells and BBECs detected a single band at 44.7 kDa in both the BECs, indicating the presence of A2AAR. In a wound healing model, we found that adenosine stimulated wound repair in cultured BBECs in a concentration-dependent manner, with an optimal closure rate observed between 4 and 6 h. Similarly, the A2AAR agonist 5′-( N-cyclopropyl)carboxamidoadenosine (CPCA) augmented wound closure, with a maximal closure rate occurring between 4 and 6 h. Inhibition of A2AAR with ZM-241385, a known A2AAR antagonist, impeded wound healing. In addition, ZM-241385 also attenuated adenosine-mediated wound repair. Kinase studies revealed that adenosine-stimulated airway repair activates PKA by ligating A2AAR. Collectively, the data suggest that the A2AAR is involved in BEC adenosine-stimulated wound healing and may prove useful in understanding purinergic-mediated actions on airway epithelial repair.
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Wang, Jianjie, and Virginia H. Huxley. "Adenosine A2A receptor modulation of juvenile female rat skeletal muscle microvessel permeability." American Journal of Physiology-Heart and Circulatory Physiology 291, no. 6 (December 2006): H3094—H3105. http://dx.doi.org/10.1152/ajpheart.00526.2006.
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Little is known of the regulation of skeletal muscle microvascular exchange under resting or stimulating conditions. Adenosine (ADO) levels in skeletal muscle increase during physiological (exercise) and pathological (hypoxia, inflammation, and ischemia) conditions. Later stages of these pathologies are characterized by the loss of vascular barrier integrity. This study focused on determining which ADO receptor mediates the robust reduction in microvessel permeability to rat serum albumin ( PsRSA) observed in juvenile female rats. In microvessels isolated from abdominal skeletal muscle, ADO suffusion induced a concentration-dependent reduction in arteriolar [log(IC50) = −9.8 ± 0.2 M] and venular [log(IC50) = −8.4 ± 0.2 M] PsRSA. RT-PCR and immunoblot analysis demonstrated mRNA and protein expression of ADO A1, A2A, A2B, and A3 receptors in both vessel types, and immunofluorescence assay revealed expression of the four subtype receptors in the microvascular walls (endothelium and smooth muscle). PsRSA responses of arterioles and venules to ADO were blocked by 8-( p-sulphophenyl)theophylline, a nonselective A1 and A2 antagonist. An A2A agonist, CGS21680 , was more potent than the A1 agonist, cyclopentyladenosine, or the most-selective A2B agonist, 5′-( N-ethylcarboxamido)adenosine. The ability of CGS21680 or ADO to reduce PsRSA was abolished by the A2A antagonist, ZM241385. An adenylyl cyclase inhibitor, SQ22536, blocked the permeability response to ADO. In aggregate, these results demonstrate that, in juvenile females (before the production of the reproductive hormones), ADO enhances skeletal muscle arteriole and venule barrier function predominantly via A2A receptors using activation of adenylyl cyclase-signaling mechanisms.
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Jamwal, Sumit, Ashish Mittal, Puneet Kumar, Dana M. Alhayani, and Amal Al-Aboudi. "Therapeutic Potential of Agonists and Antagonists of A1, A2a, A2b and A3 Adenosine Receptors." Current Pharmaceutical Design 25, no. 26 (October 9, 2019): 2892–905. http://dx.doi.org/10.2174/1381612825666190716112319.
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Adenosine is a naturally occurring nucleoside and an essential component of the energy production and utilization systems of the body. Adenosine is formed by the degradation of adenosine-triphosphate (ATP) during energy-consuming processes. Adenosine regulates numerous physiological processes through activation of four subtypes of G-protein coupled membrane receptors viz. A1, A2A, A2B and A3. Its physiological importance depends on the affinity of these receptors and the extracellular concentrations reached. ATP acts as a neurotransmitter in both peripheral and central nervous systems. In the peripheral nervous system, ATP is involved in chemical transmission in sensory and autonomic ganglia, whereas in central nervous system, ATP, released from synaptic terminals, induces fast excitatory postsynaptic currents. ATP provides the energetics for all muscle movements, heart beats, nerve signals and chemical reactions inside the body. Adenosine has been traditionally considered an inhibitor of neuronal activity and a regulator of cerebral blood flow. Since adenosine is neuroprotective against excitotoxic and metabolic dysfunctions observed in neurological and ocular diseases, the search for adenosinerelated drugs regulating adenosine transporters and receptors can be important for advancement of therapeutic strategies against these diseases. This review will summarize the therapeutic potential and recent SAR and pharmacology of adenosine and its receptor agonists and antagonists.
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D’Antongiovanni, Vanessa, Matteo Fornai, Carolina Pellegrini, Laura Benvenuti, Corrado Blandizzi, and Luca Antonioli. "The Adenosine System at the Crossroads of Intestinal Inflammation and Neoplasia." International Journal of Molecular Sciences 21, no. 14 (July 18, 2020): 5089. http://dx.doi.org/10.3390/ijms21145089.
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Adenosine is a purine nucleoside, resulting from the degradation of adenosine triphosphate (ATP). Under adverse conditions, including hypoxia, ischemia, inflammation, or cancer, the extracellular levels of adenosine increase significantly. Once released, adenosine activates cellular signaling pathways through the engagement of the four known G-protein-coupled receptors, adenosine A1 receptor subtype (A1), A2A, A2B, and A3. These receptors, expressed virtually on all immune cells, mitigate all aspects of immune/inflammatory responses. These immunosuppressive effects contribute to blunt the exuberant inflammatory responses, shielding cells, and tissues from an excessive immune response and immune-mediated damage. However, a prolonged persistence of increased adenosine concentrations can be deleterious, participating in the creation of an immunosuppressed niche, ideal for neoplasia onset and development. Based on this evidence, the present review has been conceived to provide a comprehensive and critical overview of the involvement of adenosine system in shaping the molecular mechanisms underlying the enteric chronic inflammation and in promoting the generation of an immunosuppressive niche useful for the colorectal tumorigenesis.
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Guieu, Régis, Clara Degioanni, Julien Fromonot, Lucille De Maria, Jean Ruf, Jean Claude Deharo, and Michele Brignole. "Adenosine, Adenosine Receptors and Neurohumoral Syncope: From Molecular Basis to Personalized Treatment." Biomedicines 10, no. 5 (May 13, 2022): 1127. http://dx.doi.org/10.3390/biomedicines10051127.
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Adenosine is a ubiquitous nucleoside that is implicated in the occurrence of clinical manifestations of neuro-humoral syncope (NHS). NHS is characterized by a drop in blood pressure due to vasodepression together with cardio inhibition. These manifestations are often preceded by prodromes such as headaches, abdominal pain, feeling of discomfort or sweating. There is evidence that adenosine is implicated in NHS. Adenosine acts via four subtypes of receptors, named A1 (A1R), A2A (A2AR), A2B (A2BR) and A3 (A3R) receptors, with all subtypes belonging to G protein membrane receptors. The main effects of adenosine on the cardiovascular system occurs via the modulation of potassium ion channels (IK Ado, K ATP), voltage-gate calcium channels and via cAMP production inhibition (A1R and A3R) or, conversely, through the increased production of cAMP (A2A/BR) in target cells. However, it turns out that adenosine, via the activation of A1R, leads to bradycardia, sinus arrest or atrioventricular block, while the activation of A2AR leads to vasodilation; these same manifestations are found during episodes of syncope. The use of adenosine receptor antagonists, such as theophylline or caffeine, should be useful in the treatment of some forms of NHS. The aim of this review was to summarize the main data regarding the link between the adenosinergic system and NHS and the possible consequences on NHS treatment by means of adenosine receptor antagonists.
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Karl, Mike O., Johannes C. Fleischhauer, W. Daniel Stamer, Kim Peterson-Yantorno, Claire H. Mitchell, R. A. Stone, and M. M. Civan. "Differential P1-purinergic modulation of human Schlemm's canal inner-wall cells." American Journal of Physiology-Cell Physiology 288, no. 4 (April 2005): C784—C794. http://dx.doi.org/10.1152/ajpcell.00333.2004.
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Intraocular pressure is directly dependent on aqueous humor flow into, and resistance to flow out of, the eye. Adenosine has complex effects on intraocular pressure. Stimulation of A1and A2Aadenosine receptors changes intraocular pressure oppositely, likely through opposing actions on the outflow of aqueous humor. While the cellular sites regulating outflow resistance are unknown, the cells lining the inner wall of Schlemm's canal (SC) are a likely regulatory site. We applied selective adenosine receptor agonists to SC cells in vitro to compare the responses to A1and A2Astimulation. Parallel studies were conducted with human inner-wall SC cells isolated by a novel enzyme-assisted technique and with cannula-derived mixed inner- and outer-wall SC cells. A1agonists increased whole cell currents of both inner-wall and cannula-derived SC cells. An A2Aagonist reduced currents most consistently in specifically inner-wall SC cells. Those currents were also increased by A2B, but not consistently affected by A3, stimulation. A1, A2A, and A3agonists all increased SC-cell intracellular Ca2+. The electrophysiological results are consistent with the possibility that inner-wall SC cells may mediate the previously reported modulatory effects of adenosine on outflow resistance. The results are also consistent with the presence of functional A2B, as well as A1, A2A, and A3adenosine receptors in SC cells.
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Xaus, Jordi, Annabel F. Valledor, Marina Cardó, Laura Marquès, Jorge Beleta, José M. Palacios, and Antonio Celada. "Adenosine Inhibits Macrophage Colony-Stimulating Factor-Dependent Proliferation of Macrophages Through the Induction of p27kip-1 Expression." Journal of Immunology 163, no. 8 (October 15, 1999): 4140–49. http://dx.doi.org/10.4049/jimmunol.163.8.4140.
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Abstract Adenosine is produced during inflammation and modulates different functional activities in macrophages. In murine bone marrow-derived macrophages, adenosine inhibits M-CSF-dependent proliferation with an IC50 of 45 μM. Only specific agonists that can activate A2B adenosine receptors such as 5′-N-ethylcarboxamidoadenosine, but not those active on A1 (N6-(R)-phenylisopropyladenosine), A2A ([p-(2-carbonylethyl)phenylethylamino]-5′-N-ethylcarboxamidoadenosine), or A3 (N6-(3-iodobenzyl)adenosine-5′-N-methyluronamide) receptors, induce the generation of cAMP and modulate macrophage proliferation. This suggests that adenosine regulates macrophage proliferation by interacting with the A2B receptor and subsequently inducing the production of cAMP. In fact, both 8-Br-cAMP (IC50 85 μM) and forskolin (IC50 7 μM) inhibit macrophage proliferation. Moreover, the inhibition of adenylyl cyclase and protein kinase A blocks the inhibitory effect of adenosine and its analogues on macrophage proliferation. Adenosine causes an arrest of macrophages at the G1 phase of the cell cycle without altering the activation of the extracellular-regulated protein kinase pathway. The treatment of macrophages with adenosine induces the expression of p27kip-1, a G1 cyclin-dependent kinase inhibitor, in a protein kinase A-dependent way. Moreover, the involvement of p27kip-1 in the adenosine inhibition of macrophage proliferation was confirmed using macrophages from mice with a disrupted p27kip-1 gene. These results demonstrate that adenosine inhibits macrophage proliferation through a mechanism that involves binding to A2B adenosine receptor, the generation of cAMP, and the induction of p27kip-1 expression.
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Shang, Liangcheng, Yaobiao Huang, Xin Xie, Sudan Ye, and Chun Chen. "Effect of Adenosine Receptor Antagonists on Adenosine-Pretreated PC12 Cells Exposed to Paraquat." Dose-Response 20, no. 2 (April 2022): 155932582210934. http://dx.doi.org/10.1177/15593258221093411.
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Previous studies evaluated the adenosine receptor antagonists alone to determine their effects on oxidative stress, but little is known about adenosine’s protective efficacy when oxidative injury occurs in vivo. Adenosine is a crucial signaling molecule recognized by four distinct G-protein-coupled receptors (GPCRs) (i.e., A1R, A2AR, A2BR, and A3R) and protects cells against pathological conditions. The present study was performed to evaluate the role of antagonist modulation in the setting of paraquat toxicity with adenosine pretreatment. First, PC12 cells were exposed to paraquat (850 μM) and adenosine (30 μM) to develop an in vitro model for the antagonist effect assay. Second, we found that the A1R antagonist DPCPX enhanced the viability of paraquat-induced PC12 cells that underwent adenosine pretreatment. Moreover, the A2AR antagonist ZM241385 decreased the viability of paraquat-induced PC12 cells that underwent adenosine pretreatment. Our findings indicate that adenosine protection requires a dual blockade of A1R and activation of A2AR to work at its full potential, and the A2B and A3 adenosine receptor antagonists increased paraquat-induced oxidative damage. This represents a novel pharmacological strategy based on A1/A2A interactions and can assist in clarifying the role played by AR antagonists in the treatment of neurodegenerative diseases.
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Szkotak, Artur J., Amy M. L. Ng, Jolanta Sawicka, Stephen A. Baldwin, S. F. Paul Man, Carol E. Cass, James D. Young, and Marek Duszyk. "Regulation of K+ current in human airway epithelial cells by exogenous and autocrine adenosine." American Journal of Physiology-Cell Physiology 281, no. 6 (December 1, 2001): C1991—C2002. http://dx.doi.org/10.1152/ajpcell.2001.281.6.c1991.
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The regulatory actions of adenosine on ion channel function are mediated by four distinct membrane receptors. The concentration of adenosine in the vicinity of these receptors is controlled, in part, by inwardly directed nucleoside transport. The purpose of this study was to characterize the effects of adenosine on ion channels in A549 cells and the role of nucleoside transporters in this regulation. Ion replacement and pharmacological studies showed that adenosine and an inhibitor of human equilibrative nucleoside transporter (hENT)-1, nitrobenzylthioinosine, activated K+ channels, most likely Ca2+-dependent intermediate-conductance K+ ( I K) channels. A1 but not A2 receptor antagonists blocked the effects of adenosine. RT-PCR studies showed that A549 cells expressed mRNA for I K-1 channels as well as A1, A2A, and A2B but not A3 receptors. Similarly, mRNA for equilibrative (hENT1 and hENT2) but not concentrative (hCNT1, hCNT2, and hCNT3) nucleoside transporters was detected, a result confirmed in functional uptake studies. These studies showed that adenosine controls the function of K+ channels in A549 cells and that hENTs play a crucial role in this process.
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Koscso, Balazs, Zsolt Selmeczy, Leonora Himer, Balazs Csoka, and Gyorgy Hasko. "Adenosine receptor activation augments IL-10 production by murine microglial cells (116.31)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 116.31. http://dx.doi.org/10.4049/jimmunol.186.supp.116.31.
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Abstract Microglia, the intrinsic macrophages of the central nervous system produce the anti-inflammatory cytokine IL-10 following activation with the bacterial cell wall product peptidoglycan (PGN), which is recognized by Toll-like receptor 2 (TLR2). Adenosine is an endogenous purine nucleoside that binds to specific G protein-coupled receptors (A1, A2A, A2B, and A3), and is a well known modulator of the immune system. In this study we investigated the effect of adenosine on IL-10 production by microglia. Cells were treated with adenosine, or selective adenosine receptor agonists and antagonists, in conjunction with 20 μg/ml PGN for 6 or 24 hours. Adenosine treatment augmented IL-10 production by microglia activated with PGN. The non-selective adenosine receptor agonist NECA was the most potent IL-10 inducer, and its effect was prevented by pretreatment with the A2B antagonist MRS-1754. Adenosine receptor activation augmented IL-10 mRNA levels, and this effect was prevented by blocking transcription with actinomycin D. The stimulatory effect of adenosine on IL-10 production was mediated by p38 because it was reversed with a p38 pathway inhibitor. IL-10 promoter analysis and chromatin immunoprecipitation (CHIP) experiments suggested that CREB activation is necessary for the effect of adenosine. These results demonstrate that A2B adenosine receptor activation augments IL-10 production by PGN-activated microglial cells through a p38- and CREB-mediated pre-transcriptional mechanism.
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Gharibi, Borzo, Jack Ham, and Bronwen Evans. "Adenosine A2b Receptors Induce Osteoblastogenesis Whereas A1 Receptors Induce Adipogenesis." Bone 46 (March 2010): S48—S49. http://dx.doi.org/10.1016/j.bone.2010.01.109.
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Muller, C. E., and B. Stein. "Adenosine Receptor Antagonists: Structures and Potential Therapeutic Applications." Current Pharmaceutical Design 2, no. 5 (October 1996): 501–30. http://dx.doi.org/10.2174/1381612802666221004174507.
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Adenosine Receptors (AR) are widely distributed in the human body. Four distinct AR subtypes, designated A1, A2a, A2b, and A3, have been identified on a pharmacological basis (affinity profile of agonists and antagonists; second messenger systems) as well as on a molecular level (cloning from various species, including humans). The current article focusses on recent advances in the development of subtype-selective AR antagonists, structure-activity relationships (SAR) of xanthine and non-xanthine A!-, A2a-, A2b- and A3-AR antagonists, and their in-vivo actions. Special attention is given to the cardiovascular effects mediated by AR agonists and antagonists. Potential therapeutic applications for AR ligands, particularly antagonists, in the cardiovascular area and other fields (e.g. CNS, kidney) are discussed.
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Morrison, R. Ray, Bunyen Teng, Peter J. Oldenburg, Laxmansa C. Katwa, Jurgen B. Schnermann, and S. Jamal Mustafa. "Effects of targeted deletion of A1 adenosine receptors on postischemic cardiac function and expression of adenosine receptor subtypes." American Journal of Physiology-Heart and Circulatory Physiology 291, no. 4 (October 2006): H1875—H1882. http://dx.doi.org/10.1152/ajpheart.00158.2005.
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To examine ischemic tolerance in the absence of A1 adenosine receptors (A1ARs), isolated wild-type (WT) and A1AR knockout (A1KO) murine hearts underwent global ischemia-reperfusion, and injury was measured in terms of functional recovery and efflux of lactate dehydrogenase (LDH). Hearts were analyzed by real-time RT-PCR both at baseline and at intervals during ischemia-reperfusion to determine whether compensatory expression of other adenosine receptor subtypes occurs with either A1AR deletion and/or ischemia-reperfusion. A1KO hearts had higher baseline coronary flow (CF) and left ventricular developed pressure (LVDP) than WT hearts, whereas heart rate was unchanged by A1AR deletion. After 20 min of ischemia, CF was attenuated in A1KO compared with WT hearts, and this reduction persisted throughout reperfusion. Final recovery of LVDP was decreased in A1KO hearts (54.4 ± 5.1 vs. WT 81.1 ± 3.4% preischemic baseline) and correlated with higher diastolic pressure during reperfusion. Postischemic efflux of LDH was greater in A1KO compared with WT hearts. Real-time RT-PCR demonstrated the absence of A1AR transcript in A1KO hearts, and the message for A2A, A2B, and A3 adenosine receptors was similar in uninstrumented A1KO and WT hearts. Ischemia-reperfusion increased A2B mRNA expression 2.5-fold in both WT and A1KO hearts without changing A1 or A3 expression. In WT hearts, ischemia transiently doubled A2A mRNA, which returned to preischemic level upon reperfusion, a pattern not observed in A1KO hearts. Together, these data affirm the cardioprotective role of A1ARs and suggest that induced expression of other adenosine receptor subtypes may participate in the response to ischemia-reperfusion in isolated murine hearts.
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Shakya, Ashok K., Rajashri R. Naik, Ihab M. ALMASRI, and Avneet Kaur. "Role and Function of Adenosine and its Receptors in Inflammation, Neuroinflammation, IBS, Autoimmune Inflammatory Disorders, Rheumatoid Arthritis and Psoriasis." Current Pharmaceutical Design 25, no. 26 (October 9, 2019): 2875–91. http://dx.doi.org/10.2174/1381612825666190716145206.
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The physiological effects of endogenous adenosine on various organ systems are very complex and numerous which are elicited upon activation of any of the four G-protein-coupled receptors (GPCRs) denoted as A1, A2A, A2B and A3 adenosine receptors (ARs). Several fused heterocyclic and non-xanthine derivatives are reported as a possible target for these receptors due to physiological problems and lack of selectivity of xanthine derivatives. In the present review, we have discussed the development of various new chemical entities as a target for these receptors. In addition, compounds acting on adenosine receptors can be utilized in treating diseases like inflammation, neuroinflammation, autoimmune and related diseases.
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Ryzhov, S. V., K. S. Yuryeva, K. V. Goremykin, Ye V. Korotkaya, I. V. Saltykova, Yu A. Yakovleva, Ye S. Kulikov, et al. "Adenosine-dependent regulation of paracrine factors expression in human venous blood monocytes." Bulletin of Siberian Medicine 10, no. 3 (June 28, 2011): 54–61. http://dx.doi.org/10.20538/1682-0363-2011-3-54-61.
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The flow cytometry analysis of human peripheral blood monocytes separated by a two step density gradient centrifugation is reported. The expression of mRNA level of adenosine receptor (AdoR) subtypes (A1, A2A, A2B and A3) and interleukin 6 (IL-6), interleukin 8 (IL-8) and vascular endothelial growth factor (VEGF) in monocytes were determined using real-time PCR. We found considerable variation across individuals in mRNA expression levels of paracrine factors after the stimulation of adenosine receptors. Our findings suggests the role of adenosinergic system accounted for interindividual differences in monocyte activation.
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Chandrasekaran, Balakumar, Sara Samarneh, Abdul Muttaleb Yousef Jaber, Ghadir Kassab, and Nikhil Agrawal. "Therapeutic Potentials of A2B Adenosine Receptor Ligands: Current Status and Perspectives." Current Pharmaceutical Design 25, no. 25 (October 3, 2019): 2741–71. http://dx.doi.org/10.2174/1381612825666190717105834.
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Background: Adenosine receptors (ARs) are classified as A1, A2A, A2B, and A3 subtypes belong to the superfamily of G-protein coupled receptors (GPCRs). More than 40% of modern medicines act through either activation or inhibition of signaling processes associated with GPCRs. In particular, A2B AR signaling pathways are implicated in asthma, inflammation, cancer, ischemic hyperfusion, diabetes mellitus, cardiovascular diseases, gastrointestinal disorders, and kidney disease. Methods: This article reviews different disease segments wherein A2B AR is implicated and discusses the potential role of subtype-selective A2B AR ligands in the management of such diseases or disorders. All the relevant publications on this topic are reviewed and presented scientifically. Results: This review provides an up-to-date highlight of the recent advances in the development of novel and selective A2B AR ligands and their therapeutic role in treating various disease conditions. A special focus has been given to the therapeutic potentials of selective A2B AR ligands in the management of airway inflammatory conditions and cancer. Conclusions: This systematic review demonstrates the current status and perspectives of A2B AR ligands as therapeutically useful agents that would assist medicinal chemists and pharmacologists in discovering novel and subtype-selective A2B AR ligands as potential drug candidates.
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Vincenzi, Fabrizio, Silvia Pasquini, Stefania Gessi, Stefania Merighi, Romeo Romagnoli, Pier Andrea Borea, and Katia Varani. "The Detrimental Action of Adenosine on Glutamate-Induced Cytotoxicity in PC12 Cells Can Be Shifted towards a Neuroprotective Role through A1AR Positive Allosteric Modulation." Cells 9, no. 5 (May 18, 2020): 1242. http://dx.doi.org/10.3390/cells9051242.
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Glutamate cytotoxicity is implicated in neuronal death in different neurological disorders including stroke, traumatic brain injury, and neurodegenerative diseases. Adenosine is a nucleoside that plays an important role in modulating neuronal activity and its receptors have been identified as promising therapeutic targets for glutamate cytotoxicity. The purpose of this study is to elucidate the role of adenosine and its receptors on glutamate-induced injury in PC12 cells and to verify the protective effect of the novel A1 adenosine receptor positive allosteric modulator, TRR469. Flow cytometry experiments to detect apoptosis revealed that adenosine has a dual role in glutamate cytotoxicity, with A2A and A2B adenosine receptor (AR) activation exacerbating and A1 AR activation improving glutamate-induced cell injury. The overall effect of endogenous adenosine in PC12 cells resulted in a facilitating action on glutamate cytotoxicity, as demonstrated by the use of adenosine deaminase and selective antagonists. However, enhancing the action of endogenous adenosine on A1ARs by TRR469 completely abrogated glutamate-mediated cell death, caspase 3/7 activation, ROS production, and mitochondrial membrane potential loss. Our results indicate a novel potential therapeutic strategy against glutamate cytotoxicity based on the positive allosteric modulation of A1ARs.
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Ponnoth, Dovenia S., Maryam Sharifi Sanjani, Catherine Ledent, Kevin Roush, Thomas Krahn, and S. Jamal Mustafa. "Absence of adenosine-mediated aortic relaxation in A2A adenosine receptor knockout mice." American Journal of Physiology-Heart and Circulatory Physiology 297, no. 5 (November 2009): H1655—H1660. http://dx.doi.org/10.1152/ajpheart.00192.2009.
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Adenosine mediates vascular responses through four receptor subtypes: A1, A2A, A2B, and A3. The role of A2A receptors in aortic vascular tone was investigated using A2A adenosine receptor (AR) knockout (A2AKO) and corresponding wild-type (A2AWT) mice. Isolated aortic rings from A2AWT and A2AKO mice were precontracted with phenylephrine (10−7 M), and concentration responses for adenosine analogs and selective agonists/antagonists were obtained. Nonselective adenosine analog (NECA; EC50 = 6.78 μM) and CGS-21680 (A2AAR selective agonist; EC50 = 0.013 μM) produced concentration-dependent relaxation (maximum of 25% and 28% relaxation at 10−5 M NECA and CGS-21680, respectively) in A2AWT aorta. In A2AKO aorta, NECA (EC50 = 0.075 μM) induced concentration-dependent contraction (maximum contraction of 47% at 10−6 M; P < 0.05 compared with A2AWT), whereas CGS-21680 produced no response. SCH-58261 (10−6 M; A2AAR selective antagonist) abolished both NECA- and CGS-21680-mediated vasorelaxation in A2AWT ( P < 0.05), whereas no change was observed in A2AKO. When DPCPX (10−5 M; A1 selective antagonist) was used in NECA concentration response, greater vasorelaxation was observed in A2AWT (50% vs. 25% in controls at 10−5 M; P < 0.05), whereas lower contraction was seen in A2AKO tissues (5% vs. 47% in controls at 10−6 M; P < 0.05). Aortic endothelial function, determined by response to acetylcholine, was significantly higher in WT compared with KO (66% vs. 51%; P < 0.05). BAY 60–6583 (A2B selective agonist) produced similar relaxation in both KO and WT tissues. In conclusion, A2AAR KO mice had significantly lower aortic relaxation and endothelial function, suggesting that the A2AAR plays an important role in vasorelaxation, probably through an endothelium-dependent mechanism.
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Guiol, Claire, Sarah El Harake, Julien Fromonot, Mohamed Chefrour, Marguerite Gastaldi, Yassine Alibouch, Maxime Doublier, et al. "Adenosine Receptors Profile in Fibromuscular Dysplasia." Biomedicines 10, no. 11 (November 6, 2022): 2831. http://dx.doi.org/10.3390/biomedicines10112831.
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Fibromuscular dysplasia (FMD) is a non-inflammatory vascular disease that is characterized by unexplained systemic hypertension occurring in young people, associated with arterial stenosis, aneurysm rupture, intracranial/renal infarction, and stroke. Although the gold standard for the diagnosis remains catheter-angiography, biological markers would be helpful due to the delay from first symptom to diagnosis. Adenosine is an ATP derivative, that may be implicated in FMD pathophysiology. We hypothesized that changes in adenosine blood level (ABL) and production of adenosine receptors may be associated with FMD. Using peripheral blood mononuclear cells, we evaluated A1, A2A, and A2B receptor production by Western blot, in 67 patients (17 men and 50 women, mean (range) age 55 (29–77) years and 40 controls, 10 men and 30 women, mean (range) age 56 (37–70)). ABL was evaluated by liquid chromatography, mass spectrometry. ABL was significantly higher in patients vs. controls, mean (range): 1.7 (0.7–3) µmol/L vs. controls 0.6 (0.4–0.8) µmol/L (+180%) p < 0.001. While A1R and A2AR production did not differ in patients and controls, we found an over-production of A2BR in patients: 1.70 (0.90–2.40; arbitrary units) vs. controls = 1.03 (0.70–1.40), mean + 65% (p < 0.001). A2BR production with a cut off of 1.3 arbitrary units, gives a good sensitivity and specificity for the diagnosis. Production measurement of A2BR on monocytes and ABL could help in the diagnosis, especially in atypical or with poor symptoms.
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Gao, Zhan-Guo, and Kenneth A. Jacobson. "A2B Adenosine Receptor and Cancer." International Journal of Molecular Sciences 20, no. 20 (October 17, 2019): 5139. http://dx.doi.org/10.3390/ijms20205139.
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There are four subtypes of adenosine receptors (ARs), named A1, A2A, A2B and A3, all of which are G protein-coupled receptors (GPCRs). Locally produced adenosine is a suppressant in anti-tumor immune surveillance. The A2BAR, coupled to both Gαs and Gαi G proteins, is one of the several GPCRs that are expressed in a significantly higher level in certain cancer tissues, in comparison to adjacent normal tissues. There is growing evidence that the A2BAR plays an important role in tumor cell proliferation, angiogenesis, metastasis, and immune suppression. Thus, A2BAR antagonists are novel, potentially attractive anticancer agents. Several antagonists targeting A2BAR are currently in clinical trials for various types of cancers. In this review, we first describe the signaling, agonists, and antagonists of the A2BAR. We further discuss the role of the A2BAR in the progression of various cancers, and the rationale of using A2BAR antagonists in cancer therapy.
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Tang, Lilong, Michael Parker, Qing Fei, and Rodger Loutzenhiser. "Afferent arteriolar adenosine A2a receptors are coupled to KATP in in vitro perfused hydronephrotic rat kidney." American Journal of Physiology-Renal Physiology 277, no. 6 (December 1, 1999): F926—F933. http://dx.doi.org/10.1152/ajprenal.1999.277.6.f926.
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Adenosine is known to exert dual actions on the afferent arteriole, eliciting vasoconstriction, by activating A1 receptors, and vasodilation at higher concentrations, by activating lower-affinity A2 receptors. We could demonstrate both of these known adenosine responses in the in vitro perfused hydronephrotic rat kidney. Thus, 1.0 μM adenosine elicited a transient vasoconstriction blocked by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), and 10–30 μM adenosine reversed KCl-induced vasoconstriction. However, when we examined the effects of adenosine on pressure-induced afferent arteriolar vasoconstriction, we observed a third action. In this setting, a high-affinity adenosine vasodilatory response was observed at concentrations of 10–300 nM. This response was blocked by both 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol (ZM-241385) and glibenclamide and was mimicked by 2-phenylaminoadenosine (CV-1808) (IC50 of 100 nM), implicating adenosine A2a receptors coupled to ATP-sensitive K channels (KATP). Like adenosine, 5′- N-ethylcarboxamidoadenosine (NECA) elicited both glibenclamide-sensitive and glibenclamide-insensitive vasodilatory responses. The order of potency for the glibenclamide-sensitive component was NECA > adenosine = CV-1808. Our findings suggest that, in addition to the previously described adenosine A1 and low-affinity A2b receptors, the renal microvasculature is also capable of expressing high-affinity adenosine A2areceptors. This renal adenosine receptor elicits afferent arteriolar vasodilation at submicromolar adenosine levels by activating KATP.
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Borea, Pier Andrea, Stefania Gessi, Stefania Merighi, Fabrizio Vincenzi, and Katia Varani. "Pharmacology of Adenosine Receptors: The State of the Art." Physiological Reviews 98, no. 3 (July 1, 2018): 1591–625. http://dx.doi.org/10.1152/physrev.00049.2017.
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Adenosine is a ubiquitous endogenous autacoid whose effects are triggered through the enrollment of four G protein-coupled receptors: A1, A2A, A2B, and A3. Due to the rapid generation of adenosine from cellular metabolism, and the widespread distribution of its receptor subtypes in almost all organs and tissues, this nucleoside induces a multitude of physiopathological effects, regulating central nervous, cardiovascular, peripheral, and immune systems. It is becoming clear that the expression patterns of adenosine receptors vary among cell types, lending weight to the idea that they may be both markers of pathologies and useful targets for novel drugs. This review offers an overview of current knowledge on adenosine receptors, including their characteristic structural features, molecular interactions and cellular functions, as well as their essential roles in pain, cancer, and neurodegenerative, inflammatory, and autoimmune diseases. Finally, we highlight the latest findings on molecules capable of targeting adenosine receptors and report which stage of drug development they have reached.
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Herman-de-Sousa, Carina, Ana Rita Pinheiro, Diogo Paramos-de-Carvalho, Maria Adelina Costa, Fátima Ferreirinha, Teresa Magalhães-Cardoso, Severino Ribeiro, Julie Pelletier, Jean Sévigny, and Paulo Correia-de-Sá. "Opposing Effects of Adenosine and Inosine in Human Subcutaneous Fibroblasts May Be Regulated by Third Party ADA Cell Providers." Cells 9, no. 3 (March 7, 2020): 651. http://dx.doi.org/10.3390/cells9030651.
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Human subcutaneous fibroblasts (HSCF) challenged with inflammatory mediators release huge amounts of ATP, which rapidly generates adenosine. Given the nucleoside’s putative relevance in wound healing, dermal fibrosis, and myofascial pain, we investigated the role of its precursor, AMP, and of its metabolite, inosine, in HSCF cells growth and collagen production. AMP (30 µM) was rapidly (t½ 3 ± 1 min) dephosphorylated into adenosine by CD73/ecto-5′-nucleotidase. Adenosine accumulation (t½ 158 ± 17 min) in the extracellular fluid reflected very low cellular adenosine deaminase (ADA) activity. HSCF stained positively against A2A and A3 receptors but were A1 and A2B negative. AMP and the A2A receptor agonist, CGS21680C, increased collagen production without affecting cells growth. The A2A receptor antagonist, SCH442416, prevented the effects of AMP and CGS21680C. Inosine and the A3 receptor agonist, 2Cl-IB-MECA, decreased HSCF growth and collagen production in a MRS1191-sensitive manner, implicating the A3 receptor in the anti-proliferative action of inosine. Incubation with ADA reproduced the inosine effect. In conclusion, adenosine originated from extracellular ATP hydrolysis favors normal collagen production by HSCF via A2A receptors. Inhibition of unpredicted inosine formation by third party ADA cell providers (e.g., inflammatory cells) may be a novel therapeutic target to prevent inappropriate dermal remodeling via A3 receptors activation.