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1
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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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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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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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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Shi, Yanrong, Xiaoguang Liu, Debebe Gebremedhin, John R. Falck, David R. Harder, and Raymond C. Koehler. "Interaction of Mechanisms Involving Epoxyeicosatrienoic Acids, Adenosine Receptors, and Metabotropic Glutamate Receptors in Neurovascular Coupling in Rat Whisker Barrel Cortex." Journal of Cerebral Blood Flow & Metabolism 28, no. 1 (May 23, 2007): 111–25. http://dx.doi.org/10.1038/sj.jcbfm.9600511.
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Adenosine, astrocyte metabotropic glutamate receptors (mGluRs), and epoxyeicosatrienoic acids (EETs) have been implicated in neurovascular coupling. Although A2A and A2B receptors mediate cerebral vasodilation to adenosine, the role of each receptor in the cerebral blood flow (CBF) response to neural activation remains to be fully elucidated. In addition, adenosine can amplify astrocyte calcium, which may increase arachidonic acid metabolites such as EETs. The interaction of these pathways was investigated by determining if combined treatment with antagonists exerted an additive inhibitory effect on the CBF response. During whisker stimulation of anesthetized rats, the increase in cortical CBF was reduced by approximately half after individual administration of A2B, mGluR and EET antagonists and EET synthesis inhibitors. Combining treatment of either a mGluR antagonist, an EET antagonist, or an EET synthesis inhibitor with an A2B receptor antagonist did not produce an additional decrement in the CBF response. Likewise, the CBF response also remained reduced by ∼50% when an EET antagonist was combined with an mGluR antagonist or an mGluR antagonist plus an A2B receptor antagonist. In contrast, A2A and A3 receptor antagonists had no effect on the CBF response to whisker stimulation. We conclude that (1) adenosine A2B receptors, rather than A2A or A3 receptors, play a significant role in coupling cortical CBF to neuronal activity, and (2) the adenosine A2B receptor, mGluR, and EETs signaling pathways are not functionally additive, consistent with the possibility of astrocytic mGluR and adenosine A2B receptor linkage to the synthesis and release of vasodilatory EETs.
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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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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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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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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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Cekic, Caglar, and Joel Linden. "Adenosine A2B receptor signaling in antigen presenting cells suppress anti-tumor adaptive immune responses (127.10)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 127.10. http://dx.doi.org/10.4049/jimmunol.188.supp.127.10.
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Abstract Adenosine is generated in response to cellular stress such as hypoxia and inflammation and acts as a “metabokine” to modulate immune responses and prevent tissue damage. The accumulation of high levels of adenosine in tumors activates adenosine A2A and A2B receptors on immune cells to attenuate tumor rejection. Previously, we have shown that A2BR blockade inhibits growth of syngeneic tumors by enhancing innate and adaptive immune responses. However, the cellular targets that mediate inhibition of tumor growth after A2B receptor blockade are unknown. In this study, we tested the activity of innate and adaptive immune cells isolated from bladder or melanoma tumors grown in mice reconstituted with mixed bone marrows from A2BR-/- and A2BR+/+ animals. While A2BR deficiency did not influence the activation of NK cells and T cells, A2BR-/- antigen presenting cells were activated more than A2BR-/- cells. Selective deletion of A2BRs on myeloid cells or CD11c expressing cells significantly delayed the growth of syngeneic melanoma. The results show that antigen-presenting cells are direct cellular targets for tumor growth inhibition after A2BR blockade. The results of this study have important implications for therapeutic use of A2B receptor blockade or deletion for treatment of cancer.
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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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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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Xiang, Hong-Jun, Fu-Lu Chai, De-Sheng Wang, and Ke-Feng Dou. "Downregulation of the Adenosine A2b Receptor by RNA Interference Inhibits Hepatocellular Carcinoma Cell Growth." ISRN Oncology 2011 (April 28, 2011): 1–7. http://dx.doi.org/10.5402/2011/875684.
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To investigate the biological effect of adenosine A2b receptor (A2bR) on the human hepatocellular carcinoma cell line HepG2, three A2bR siRNA constructs were transiently transfected into HepG2 cells. The results showed that A2bR siRNA reduced the levels of A2bR mRNA and protein. In order to further detect the function of A2bR, we established a stable hepatocellular carcinoma cell line (HepG2) expressing siRNA targeting the adenosine A2b receptor. Targeted RNAi significantly inhibited tumor cell growth in vitro, and flow cytometry (FCM) showed that significantly more cells expressing A2bR siRNA were in the G0/G1 phase compared to the untransfected group ((89.56%±3.15%) versus (56.19%±1.58%), P<0.01). These results indicated that silencing the expression of adenosine A2b receptor in HepG2 cells can suppress cell growth effectively by blocking the cell cycle. Downregulation of adenosine A2b receptor gene expression with RNA interference could be a new approach to hepatocellular carcinoma therapy.
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Csoka, Balazs, Balazs Koscso, Gabor Toro, Endre Kokai, Zoltan Nemeth, Peter Bai, and Gyorgy Hasko. "A2B adenosine receptors inhibit obesity-induced adipose tissue inflammation (P3109)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 43.16. http://dx.doi.org/10.4049/jimmunol.190.supp.43.16.
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Abstract Obesity promotes adipose tissue inflammation, which in turn causes insulin resistance in target organs by dysregulation of adipokine release and by increased classical and decreased alternative macrophage activation. Because A2B adenosine receptors are important regulators of macrophage activation, we examined the role of A2B adenosine receptors in diet-induced inflammation and insulin resistance. A2B receptor deletion impaired glucose metabolism in mice fed chow but not high fat diet. This impaired glucose homeostasis in A2B receptor deficient mice was paralleled by increased classical macrophage activation and inhibited alternative macrophage activation. The expression of alternative macrophage activation-specific transcriptions factors, including CCAAT/enhancer binding protein β, interferon regulatory factor 4, and peroxisome proliferator-activated receptor γ was decreased in A2B receptor deficient mice. Furthermore, in in vitro studies we found that activation of A2B receptors decreased free fatty acid-induced classical macrophage activation and increased IL-4-induced alternative macrophage activation. Therefore, therapeutic strategies targeting A2A and A2B receptors hold promise for preventing and/or treating obesity-related metabolic abnormalities.
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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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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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Olanrewaju, Hammed A., W. Qin, I. Feoktistov, Jean-Luc Scemama, and S. Jamal Mustafa. "Adenosine A2A and A2B receptors in cultured human and porcine coronary artery endothelial cells." American Journal of Physiology-Heart and Circulatory Physiology 279, no. 2 (August 1, 2000): H650—H656. http://dx.doi.org/10.1152/ajpheart.2000.279.2.h650.
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We investigated the role of the cAMP link to the signal transduction mechanism coupled with adenosine A2A and A2Breceptors in cultured human coronary artery endothelial cells (HCAEC) and porcine coronary artery endothelial cells (PCAEC). 2-[4-[2-{2-[(4-aminophenyl)methylcarbonylamino]ethylaminocarbonyl}ethyl]phenyl]ethylamino-5′- ethylcarboxamidoadenosine (125I-PAPA-APEC) (PAPA-APEC) was used to demonstrate the specific binding in PCAEC membranes. The specific binding was saturable and reversible with a maximal number of binding sites (Bmax) of 240 fmol/mg protein, and scatchard analysis revealed a single class of binding site with an equilibrium dissociation constant ( K d) of 1.17 ± 0.035 nM. In competition experiments, adenosine receptor agonists showed the following order of potency (based on IC50): 5′-( N-ethylcarboxamido)adenosine (NECA) ≥ CGS-21680 > 2-chloroadenosine. This order appears to be consistent with the A2 adenosine receptor classification. We also studied the effects of adenosine agonists on the accumulation of cAMP as an indirect approach to show the presence of functional A2 receptors. Similarly, the same adenosine agonists (10−7-10−4 M) elicited the production of cAMP in intact endothelial cells in a dose-dependent manner, exhibiting consistently with the A2 adenosine receptor classification. A selective A2A adenosine receptor antagonist (ZM-241385, 10−8 M) significantly inhibited the effect of CGS-21680 on cAMP but only partly inhibited the effect of NECA, suggesting the presence of both A2A and A2Breceptors. Western blot analysis further showed the immunoreactivity of A2A and A2B receptor at 45 and 36 kDa, respectively, in both HCAEC and PCAEC. Direct evidence for the presence of A2A and A2B receptors in cultured HCAEC and PCAEC by reverse transcription-polymerase chain reaction (RT-PCR), revealed expected PCR product sizes (205 and 173 bp) for A2A and A2B receptors in HCAEC and PCAEC, respectively. The data show that adenylate cyclase-coupled adenosine A2A and A2B receptors are present in coronary endothelial cells.
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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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Cekic, Caglar, Ali Can Savas, Merve Kayhan, Altay Koyas, and Imran Akdemir. "Targeting adenosine A2A receptors to improve vaccine efficacy." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 79.22. http://dx.doi.org/10.4049/jimmunol.198.supp.79.22.
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Abstract Activation of immune cells is associated with increased expression of adenosine receptors. Extracellular adenosine is present in primary and secondary lymphoid organs and limit the amplitude of immune responses suggesting that antagonists for adenosine receptors can be targeted to improve the efficacy of vaccines. Here we showed that vaccine adjuvant Monophosphoryl Lipid A (MPLA) strongly increased adenosine A2A and adenosine A2B receptor expression in primary macrophages and dendritic cells. Adenosine A2A but not adenosine A2B receptor blockade significantly increased both numbers and percentages of antigen specific endogenous T cells in both spleen and draining lymph nodes after primary immunizations with MPLA and ovalbumin. We observed a similar increase in both endogenous or adoptively transferred T cells in mice with myeloid-specific deletion of A2A receptors after primary immunization. Adenosine receptor blockade significantly increased the total IgG titers and IgG2c/IgG1 ratio after rechallenge with ovalbumin. These results suggest that adenosine A2A receptor blockade potentially improve vaccine efficacy by promoting both cellular and humoral immune responses and promoting Th1 type immunity. Our results also suggest that A2ARs on antigen presenting cells are important targets to improve vaccine efficacy by adenosine A2A receptor blockade. These findings have important implications for the design of novel and more efficacious vaccine formulations.
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Ruiz-García, Almudena, Eva Monsalve, Laura Novellasdemunt, Àurea Navarro-Sabaté, Anna Manzano, Samuel Rivero, Antonio Castrillo, et al. "Cooperation of Adenosine with Macrophage Toll-4 Receptor Agonists Leads to Increased Glycolytic Flux through the Enhanced Expression of PFKFB3 Gene." Journal of Biological Chemistry 286, no. 22 (April 4, 2011): 19247–58. http://dx.doi.org/10.1074/jbc.m110.190298.
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Macrophages activated through Toll receptor triggering increase the expression of the A2A and A2B adenosine receptors. In this study, we show that adenosine receptor activation enhances LPS-induced pfkfb3 expression, resulting in an increase of the key glycolytic allosteric regulator fructose 2,6-bisphosphate and the glycolytic flux. Using shRNA and differential expression of A2A and A2B receptors, we demonstrate that the A2A receptor mediates, in part, the induction of pfkfb3 by LPS, whereas the A2B receptor, with lower adenosine affinity, cooperates when high adenosine levels are present. pfkfb3 promoter sequence deletion analysis, site-directed mutagenesis, and inhibition by shRNAs demonstrated that HIF1α is a key transcription factor driving pfkfb3 expression following macrophage activation by LPS, whereas synergic induction of pfkfb3 expression observed with the A2 receptor agonists seems to depend on Sp1 activity. Furthermore, levels of phospho-AMP kinase also increase, arguing for increased PFKFB3 activity by phosphorylation in long term LPS-activated macrophages. Taken together, our results show that, in macrophages, endogenously generated adenosine cooperates with bacterial components to increase PFKFB3 isozyme activity, resulting in greater fructose 2,6-bisphosphate accumulation. This process enhances the glycolytic flux and favors ATP generation helping to develop and maintain the long term defensive and reparative functions of the macrophages.
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Mirabet, M., C. Herrera, O. J. Cordero, J. Mallol, C. Lluis, and R. Franco. "Expression of A2B adenosine receptors in human lymphocytes: their role in T cell activation." Journal of Cell Science 112, no. 4 (February 15, 1999): 491–502. http://dx.doi.org/10.1242/jcs.112.4.491.
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Extracellular adenosine has a key role in the development and function of the cells of the immune system. Many of the adenosine actions seem to be mediated by specific surface receptors positively coupled to adenylate cyclase: A2A and A2B. Despite the fact that A2A receptors (A2ARs) can be easily studied due to the availability of the specific agonist CGS21680, a pharmacological and physiological characterization of adenosine A2B receptors (A2BRs) in lymphocytes has not been possible due to the lack of suitable reagents. Here we report the generation and characterization of a polyclonal antipeptide antibody raised against the third extracellular loop of the A2BR human clone which is useful for immunocytochemical studies. This antibody has permitted the detection of A2BR+ cells in lymphocyte samples isolated from human peripheral blood. The pharmacology of cAMP-producing compounds is consistent with the presence of functional A2BRs but not of A2A receptors in these human cells. The percentage of A2BR-expressing cells was similar in the CD4(+) or CD8(+) T cell subpopulations. Interestingly activation signals delivered by either phytohemagglutinin or anti-T cell receptor/CD3 complex antibodies led to a significant increase in both the percentage of cells expressing the receptor and the intensity of the labeling. These receptors are functional since interleukin-2 production in these cells is reduced by NECA but not by R-PIA or CGS21680. These results show that A2BR expression is regulated in T cell activation and suggest that the role of adenosine in lymphocyte deactivation is mediated by A2BRs.
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Chen, Yinghong, Sara Epperson, Lala Makhsudova, Bruce Ito, Jorge Suarez, Wolfgang Dillmann, and Francisco Villarreal. "Functional effects of enhancing or silencing adenosine A2b receptors in cardiac fibroblasts." American Journal of Physiology-Heart and Circulatory Physiology 287, no. 6 (December 2004): H2478—H2486. http://dx.doi.org/10.1152/ajpheart.00217.2004.
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Cardiac fibroblasts (CF) express adenosine (ADO) receptors, and pharmacological evidence suggests the possible involvement of the A2 (A2a and A2b) receptor (A2aR and A2bR) subtypes in inhibiting cell functions involved in fibrosis. The main objective of this study was to define the contributions of A2a and/or A2b receptors in modulating ADO-induced decreases in CF functions. For this purpose, CF were either treated pharmacologically or had the A2aR or A2bR levels modified through the use of recombinant adenovirus or siRNA. The assessment of mRNA expression in adult rat CF yielded evidence for A1R, A2bR, A2aR, and A3R. Endogenously or exogenously enhanced ADO significantly inhibits CF proliferation, collagen, and protein synthesis. A2R and A2aR agonists, although capable of inhibiting CF protein and collagen synthesis, were unable to define the contributions derived from A2aR or A2bR. Overexpression of A2bR in CF yielded significant decreases in basal levels of collagen and protein synthesis and correlated with increases in cAMP levels. However, at higher doses of ADO receptor agonists, significant increases in protein and collagen synthesis were observed. CF with underexpression of A2bR yielded increases in protein and collagen synthesis. In contrast, A2aR underexpression did not modify ADO-induced decreases in CF protein or collagen synthesis. In conclusion, results derived from the molecular manipulation of receptor levels indicate that A2bR are critically involved in ADO-mediated inhibition of CF functions.
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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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Ngai, Al C., Ellicia F. Coyne, Joseph R. Meno, G. Alexander West, and H. Richard Winn. "Receptor subtypes mediating adenosine-induced dilation of cerebral arterioles." American Journal of Physiology-Heart and Circulatory Physiology 280, no. 5 (May 1, 2001): H2329—H2335. http://dx.doi.org/10.1152/ajpheart.2001.280.5.h2329.
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The purpose of this study was to investigate the receptor subtypes that mediate the dilation of rat intracerebral arterioles elicited by adenosine. Penetrating arterioles were isolated from the rat brain, cannulated with the use of a micropipette system, and luminally pressurized to 60 mmHg. Both adenosine and the A2A receptor-selective agonist CGS-21680 induced dose-dependent vasodilation (−logEC50: 6.5 ± 0.2 and 8.6 ± 0.3, respectively). However, adenosine, which is capable of activating both A2A and A2B receptors, caused a greater maximal dilation than CGS-21680. The A2Areceptor-selective antagonist ZM-241385 (0.1 μM) only partially inhibited the dilation induced by adenosine but almost completely blocked CGS-21680-induced dilation. Neither 8-cyclopentyl-1,3-dipropylxanthine (0.1 μM), an A1receptor-selective antagonist, nor MRS-1191 (0.1 μM), an A3 receptor-selective antagonist, attenuated adenosine dose responses. Moreover, ZM-241385 had no effect on the dilation induced by ATP (10 μM) or acidic (pH 6.8) buffer. We concluded that the A2A receptor subtype mediates adenosine-induced dilation of intracerebral arterioles in the rat brain. Furthermore, our results suggest that A2B receptors may also participate in the dilation response to adenosine.
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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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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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Cekic, Caglar, Duygu Sag, and Joel Linden. "Aminophylline inhibits breast and bladder tumor growth in mice due to CXCR3-dependent adenosine A2B receptor blockade (165.32)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 165.32. http://dx.doi.org/10.4049/jimmunol.186.supp.165.32.
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Abstract The activation of adenosine A2A or A2B receptors on immune cells inhibits their ability to suppress tumor growth. In this study, we evaluated the anti-tumor effects of aminophyllilne (AMO) a nonselective antagonist of A2A and A2B receptors that is used clinically to treat asthma. Intra-tumor injection of AMO inhibited the growth of syngeneic MB49 bladder cells subcutaneously injected into C57BL/6 mice and the growth and lung metastasis of luminescent syngeneic 4T1 breast tumor cells inoculated into the mammary fat pats of Balb/c mice. Although AMO inhibited the growth of MB49 in A2AR-/- mice it failed to do so in Rag1-/-, A2BR-/- or CXCR3-/- mice. The selective deletion of the A2BR or CXCR3 from bone marrow cells also blocked tumor suppression by AMO. Transcript levels of interferon-γ and CXCL10, and activation of CD4+ and CD8+ T cells, were increased in tumors treated with AMO, while numbers of CD34+/CD45- endothelial cell precursors were decreased. We conclude that: 1) the anti-tumor effects of non-selective adenosine receptor blockade by AMO are primarily mediated by the A2BR; 2) CXCR3 receptors are required for anti-tumor effects of AMO and influence both T cell trafficking and chemokine-mediated angiogenesis; and 3) AMO may be useful for proof-of-principle studies to determine the efficacy of adenosine receptor antagonists as tumor suppressors alone or in conjunction with tumor vaccines.
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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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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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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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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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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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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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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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Cekic, Caglar, Imran Akdemir, Altay Koyas, Merve Kayhan, and Ali Can Savas. "Adenosine regulation of danger signaling." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 222.14. http://dx.doi.org/10.4049/jimmunol.198.supp.222.14.
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Abstract Metabolic and immune related activities converge as main triggers of adenosine accumulation in extracellular space. Adenosine by engaging adenosine A2A and A2B receptors strongly suppresses innate and adaptive immune responses. Although adenosine receptors are being targeted in preclinical and clinical studies how different danger signals are regulated by adenosine is poorly understood. Here we showed that adenosine receptor stimulation strongly inhibited inflammatory responses while sparing type-I interferon responses downstream of different danger signals in dendritic cells and macrophages. Mechanistically, danger signals associated with MyD88-dependent inflammatory pathways such as LPS and CpG but not the danger signals associated with IRF3/Type-I interferon pathways such as pA:U and cGAMP increase the expression adenosine A2A and A2B receptors. Adenosine was shown to increase the expression of NR4A nuclear hormone receptors to inhibit NF-κB activation. Although adenosine did not influence NF-κB phosphoactivation expression of anti-inflammatory NR4A1 was increased after adenosine receptor stimulation in the presence of TLR ligands known to activate MyD88 pathway but not in the presence of cGAMP and pA:U. Overall these results indicate that there is a differential modulation of danger signaling by adenosine rather than overall supression. Our results have important implications for developing combinatorial approaches to target adenosine and danger signaling pathways to cure immune-related diseases.
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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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Shin, Hwa Kyoung, Yung Woo Shin, and Ki Whan Hong. "Role of adenosine A2B receptors in vasodilation of rat pial artery and cerebral blood flow autoregulation." American Journal of Physiology-Heart and Circulatory Physiology 278, no. 2 (February 1, 2000): H339—H344. http://dx.doi.org/10.1152/ajpheart.2000.278.2.h339.
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This study was aimed to investigate the underlying mechanism of vasodilation induced by the activation of A2B adenosine receptors in relation to cerebral blood flow (CBF) autoregulation. Changes in pial arterial diameters were observed directly through a closed cranial window. N ω-nitro-l-arginine methyl ester (l-NAME, nitric oxide synthase inhibitor) significantly suppressed the concentration-dependent vasodilations induced by adenosine and 5′- N-ethylcarboxamido-adenosine (NECA) but not the vasodilation by CGS-21680 (A2A-receptor agonist). Moreover, NECA-induced vasodilation was suppressed by alloxazine (1 μmol/l) but not by ZM-241385 (1 μmol/l, A2Aantagonist), which suggests mediation by A2B- receptor activation. Otherwise, the level of nitrite/nitrate was concentration dependently increased in the artificial cerebrospinal fluid (CSF) when adenosine and NECA were suffused over the cortical surface.l-NAME and alloxazine, but not ZM-241385, largely inhibited their releases. The lower limit of CBF autoregulation was little affected following pretreatment with l-NAME or alloxazine. Thus it is suggested that adenosine-induced vasodilation via activation of A2B-adenosine receptors of the rat pial artery is coupled to the production of nitric oxide, which contributes little to CBF autoregulation.
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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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Müller, Christa E. "Tools and Drugs for Purine-Binding Targets—Important Players in Inflammation and Cancer." Proceedings 22, no. 1 (August 7, 2019): 33. http://dx.doi.org/10.3390/proceedings2019022033.
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Despite decades of research, only few drugs have been approved that interact with purine receptors. Recently, new hypes and hopes have been created in the field, mainly due to the gold rush fever in immuno-oncology. Adenosine is one of the strongest immunosuppressant agents of the innate immune system. Cancer cells and tissues can release large amounts of ATP, which is immediately hydrolyzed by ectonucleotidases. These ecto-enzymes, including ectonucleotide pyrophosphatase/phosphodiesterase 1 (NPP1, CD203a), ectonucleoside diphosphohydrolase 1 (NTPDase1, CD39), and ecto-5′-nucleotidase (CD73), are upregulated on many cancer cells, leading to the production of adenosine. The cloud of adenosine formed around cancer tissues contributes to immune escape by interacting with adenosine A2A and A2B receptor subtypes (A2AAR, A2BAR) on immune cells. In addition, activation of A2BARs by adenosine enhances cancer cell proliferation, metastasis, and angiogenesis. Blockade of A2A and A2B adenosine receptors and/or inhibition of adenosine formation by blocking ectonucleotidases are being pursued as novel principles that activate the immune system to defeat cancer. Recent progress in the development of adenosine receptor antagonists and ectonucleotidase inhibitors will be presented and discussed.
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Kusano, Yoshikazu, German Echeverry, Greg Miekisiak, Tobias B. Kulik, Shimon N. Aronhime, Jiang F. Chen, and H. Richard Winn. "Role of Adenosine A2 Receptors in Regulation of Cerebral Blood Flow during Induced Hypotension." Journal of Cerebral Blood Flow & Metabolism 30, no. 4 (November 18, 2009): 808–15. http://dx.doi.org/10.1038/jcbfm.2009.244.
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The mechanisms responsible for vascular autoregulation in the brain during changes in mean arterial blood pressure are ambiguous. Potentially, adenosine, a purine nucleoside and potent vasodilator, may be involved as earlier studies have documented an increase in brain adenosine concentrations with cerebral ischemia and hypotension. Consequently, we tested the hypothesis that adenosine is involved in vasodilatation during hypotension within the autoregulatory range (>50 mm Hg) by exposing adenosine 2a receptor (A2aR) knockout and wild type (WT) mice to short (2 to 5 mins) periods of hypotension. We found that autoregulation was significantly ( P<0.05) impaired by 29% in A2a knockout mice as compared with WT animals. Furthermore, the A2R antagonist (A2a>A2b:10–85>1), ZM-241385, in a dose (1, 5, 10 mg/kg, intraperitoneally)-related manner, attenuated autoregulation in WT mice. In knockout mice treated with ZM-2413585 (5 and 10 mg/kg), autoregulation was further impaired indicating that A2b receptors also participated in cerebral vasodilatation. Treatment with dipyridamole (1.0 mg/kg) that increases extracellular concentrations of adenosine improved autoregulation in the A2aR knockout mice. We would conclude that adenosine through both A2a and A2b receptors is involved in physiologic vascular regulation during hypotension even within the autoregulatory range.
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Kini, Radhika, Meenakshi Subramanian, Akiko Ohta, Michail Sitkovsky, and Akio Ohta. "Physiological control of NKT cell activation by extracellular adenosine via A2B adenosine receptor (138.27)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 138.27. http://dx.doi.org/10.4049/jimmunol.184.supp.138.27.
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Abstract Negative regulatory mechanism of immune responses is essential to prevent excessive inflammatory tissue injury. Adenosine involves in physiological down-regulation of inflammation via A2A adenosine receptor (A2AR). In this study, we provide evidence that A2B adenosine receptor (A2BR) is also important in the physiological control of hepatic inflammation. Acute hepatitis induced by intravenous concanavalin A (Con A) injection was significantly more severe in A2BR-/- mice than in wild-type mice. The exaggerated inflammation in A2BR-/- mice accompanied higher levels of IL-4 from NKT cells suggesting A2BR-mediated suppression of NKT cell activation. In vitro activation of NKT cells by α-galactosylceramide (α-GalCer) showed that stimulation of A2BR is inhibitory to NKT cell activation. Furthermore, injection of α-GalCer induced higher serum cytokine levels and stronger liver damage in A2BR-/- mice. These results show that the lack of A2BR diminished negative regulatory mechanism of NKT cells by endogenously produced adenosine and, therefore, caused more severe acute hepatitis. Indeed, transfer of A2BR-/- NKT cells into RAG2-/- mice resulted in stronger Con A-induced liver injury than wild-type NKT cells. There have been controversial reports regarding the role of A2BR in inflammation. Our results demonstrate that NKT cell-mediated immune responses are under the physiological control of extracellular adenosine through A2BR signaling.
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Wang, Lixin, Vasantha Kolachala, Baljit Walia, Srividya Balasubramanian, Randy A. Hall, Didier Merlin, and Shanthi V. Sitaraman. "Agonist-induced polarized trafficking and surface expression of the adenosine 2b receptor in intestinal epithelial cells: role of SNARE proteins." American Journal of Physiology-Gastrointestinal and Liver Physiology 287, no. 5 (November 2004): G1100—G1107. http://dx.doi.org/10.1152/ajpgi.00164.2004.
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Adenosine, acting through the A2b receptor, induces vectorial chloride and IL-6 secretion in intestinal epithelia and may play an important role in intestinal inflammation. We have previously shown that apical or basolateral adenosine receptor stimulation results in the recruitment of the A2b receptor to the plasma membrane. In this study, we examined domain specificity of recruitment and the role of soluble N-ethylmaleimide (NEM) attachment receptor (SNARE) proteins in the agonist-mediated recruitment of the A2b receptor to the membrane. The colonic epithelial cell line T84 was used because it only expresses the A2b-subtype adenosine receptor. Cell fractionation, biotinylation, and electron microscopic studies showed that the A2b receptor is intracellular at rest and that apical or basolateral adenosine stimulation resulted in the recruitment of the receptor to the apical membrane. Upon agonist stimulation, the A2b receptor is enriched in the vesicle fraction containing vesicle-associated membrane protein (VAMP)-2. Furthermore, in cells stimulated with apical or basolateral adenosine, we demonstrate a complex consisting of VAMP-2, soluble NEM-sensitive factor attachment protein (SNAP)-23, and A2b receptor that is coimmunoprecipitated in cells stimulated with adenosine within 5 min and is no longer detected within 15 min. Inhibition of trafficking with NEM or nocodazole inhibits cAMP synthesis induced by apical or basolateral adenosine by 98 and 90%, respectively. cAMP synthesis induced by foskolin was not affected, suggesting that generalized signaling is not affected under these conditions. Collectively, our data suggest that 1) the A2b receptor is intracellular at rest; 2) apical or basolateral agonist stimulation induces recruitment of the A2b receptor to the apical membrane; 3) the SNARE proteins, VAMP-2 and SNAP-23, participate in the recruitment of the A2b receptor; and 4) the SNARE-mediated recruitment of the A2b receptor may be required for its signaling.
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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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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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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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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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Lindemann, Marcel, Rareş-Petru Moldovan, Sonja Hinz, Winnie Deuther-Conrad, Daniel Gündel, Sladjana Dukic-Stefanovic, Magali Toussaint, et al. "Development of a Radiofluorinated Adenosine A2B Receptor Antagonist as Potential Ligand for PET Imaging." International Journal of Molecular Sciences 21, no. 9 (April 30, 2020): 3197. http://dx.doi.org/10.3390/ijms21093197.
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The adenosine A2B receptor has been proposed as a novel therapeutic target in cancer, as its expression is drastically elevated in several tumors and cancer cells. Noninvasive molecular imaging via positron emission tomography (PET) would allow the in vivo quantification of this receptor in pathological processes and most likely enable the identification and clinical monitoring of respective cancer therapies. On the basis of a bicyclic pyridopyrimidine-2,4-dione core structure, the new adenosine A2B receptor ligand 9 was synthesized, containing a 2-fluoropyridine moiety suitable for labeling with the short-lived PET radionuclide fluorine-18. Compound 9 showed a high binding affinity for the human A2B receptor (Ki(A2B) = 2.51 nM), along with high selectivities versus the A1, A2A, and A3 receptor subtypes. Therefore, it was radiofluorinated via nucleophilic aromatic substitution of the corresponding nitro precursor using [18F]F-/K2.2.2./K2CO3 in DMSO at 120 °C. Metabolic studies of [18F]9 in mice revealed about 60% of radiotracer intact in plasma at 30 minutes p.i. A preliminary PET study in healthy mice showed an overall biodistribution of [18F]9, corresponding to the known ubiquitous but low expression of the A2B receptor. Consequently, [18F]9 represents a novel PET radiotracer with high affinity and selectivity toward the adenosine A2B receptor and a suitable in vivo profile. Subsequent studies are envisaged to investigate the applicability of [18F]9 to detect alterations in the receptor density in certain cancer-related disease models.
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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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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.