Activation of Adenylyl Cyclase Causes Stimulation of Adenosine Receptors

Pleli, Thomas; Ferreiròs, Nerea; Thomas, Dominique; Dvořák, Karel; Biondi, Ricardo M.; Heringdorf, Dagmar Meyer zu; Zeuzem, Stefan; Geißlinger, Gerd; Zimmermann, Herbert; Waidmann, Oliver; Piiper, Albrecht

doi:10.1159/000488270

Cited by 24 publications

(15 citation statements)

References 53 publications

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“…In turn, cAMP can feed back on AdoR expression. For example, high levels of cAMP induced by agents that trigger Gs-protein coupled receptors, upregulates expression of A 2 AdoR in PC12 tumor cells ( 84 ). This cycle may therefore vigorously enhance Ado mediated suppressive effects in cells, as cAMP triggered upregulation of AdoR provides a means that leads to an even more sustained cAMP production.…”

Section: Signaling Of Ador In Dcsmentioning

confidence: 99%

ATP and Its Metabolite Adenosine as Regulators of Dendritic Cell Activity

2018

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Adenosine (Ado) is a well-studied neurotransmitter, but it also exerts profound immune regulatory functions. Ado can (i) actively be released by various cells into the tissue environment and can (ii) be produced through the degradation of extracellular ATP by the concerted action of CD39 and CD73. In this sequence of events, the ectoenzyme CD39 degrades ATP into ADP and AMP, respectively, and CD73 catalyzes the last step leading to the production of Ado. Extracellular ATP acts as a “danger” signal and stimulates immune responses, i.e. by inflammasome activation. Its degradation product Ado on the other hand acts rather anti-inflammatory, as it down regulates functions of dendritic cells (DCs) and dampens T cell activation and cytokine secretion. Thus, the balance of proinflammatory ATP and anti-inflammatory Ado that is regulated by CD39+/CD73+ immune cells, is important for decision making on whether tolerance or immunity ensues. DCs express both ectoenzymes, enabling them to produce Ado from extracellular ATP by activity of CD73 and CD39 and thus allow dampening of the proinflammatory activity of adjacent leukocytes in the tissue. On the other hand, as most DCs express at least one out of four so far known Ado receptors (AdoR), DC derived Ado can also act back onto the DCs in an autocrine manner. This leads to suppression of DC functions that are normally involved in stimulating immune responses. Moreover, ATP and Ado production thereof acts as “find me” signal that guides cellular interactions of leukocytes during immune responses. In this review we will state the means by which Ado producing DCs are able to suppress immune responses and how extracellular Ado conditions DCs for their tolerizing properties.

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Section: Signaling Of Ador In Dcsmentioning

confidence: 99%

ATP and Its Metabolite Adenosine as Regulators of Dendritic Cell Activity

2018

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“…The conversion of eATP to eAdo is mediated by cell surface ectonucleotidases CD39 and CD73 expressed in the hematopoietic microenvironment and on hematopoietic stem/progenitor cells (HSPCs) [1,[4][5][6][7][8]. The four P1 receptor subtypes A 1 , A 2A , A 2B, and A 3 are classified based on their ability to either stimulate or inhibit adenylate cyclase activity [1,2,4,9]. While A 1 receptors coupled to G i/o proteins decrease cyclic AMP (cAMP) levels, the A 2 adenosine receptors coupled to G s proteins stimulate adenylate cyclase activity [2,3,5,9].…”

Section: Introductionmentioning

confidence: 99%

Extracellular Adenosine (eAdo) - A2B Receptor Axis Inhibits in Nlrp3 Inflammasome-dependent Manner Trafficking of Hematopoietic Stem/progenitor Cells

Thapa

Abdelbaset‐Ismail

Chumak

et al. 2022

Stem Cell Rev and Rep

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We postulated that mobilization, homing, and engraftment of hematopoietic stem/progenitor cells (HSCPs) is facilitated by a state of sterile inflammation induced in bone marrow (BM) after administration of pro-mobilizing drugs or in response to pre-transplant myeloablative conditioning. An important role in this phenomenon plays purinergic signaling that by the release of extracellular adenosine triphosphate (eATP) activates in HSPCs and in cells in the hematopoietic microenvironment an intracellular pattern recognition receptor (PPR) known as Nlrp3 inflammasome. We reported recently that its deficiency results in defective trafficking of HSPCs. Moreover, it is known that eATP after release into extracellular space is processed by cell surface expressed ectonucleotidases CD39 and CD73 to extracellular adenosine (eAdo) that in contrast to eATP shows an anti-inflammatory effect. Based on data that the state of sterile inflammation promotes trafficking of HSPCs, and since eAdo is endowed with anti-inflammatory properties we become interested in how eAdo will affect the mobilization, homing, and engraftment of HSPCs and which of eAdo receptors are involved in these processes. As expected, eAdo impaired HSPCs trafficking and this occurred in autocrine- and paracrine-dependent manner by direct stimulation of these cells or by affecting cells in the BM microenvironment. We report herein for the first time that this defect is mediated by activation of the A2B receptor and a specific inhibitor of this receptor improves eAdo-aggravated trafficking of HSPCs. To explain this at the molecular level eAdo-A2B receptor interaction upregulates in HSPCs in NF-kB-, NRF2- and cAMP-dependent manner heme oxygenase-1 (HO-1), that is Nlrp3 inflammasome inhibitor. This corroborated with our analysis of proteomics signature in murine HSPCs exposed to eAdo that revealed that A2B inhibition promotes cell migration and proliferation. Based on this we postulate that blockage of A2B receptor may accelerate the mobilization of HSPCs as well as their hematopoietic reconstitution and this approach could be potentially considered in the future to be tested in the clinic. Graphical Abstract

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“…The stepwise dephosphorylation of ATP towards adenosine is mediated by TNAP, ENPP1, CD39, and CD73 (Figure 1) [112,113]. The second contribution to the adenosine pool comes from adenylate cyclase (AC) activation and the generation of intracellular cyclic AMP (cAMP), cAMP efflux through multidrug resistance protein 4 (ABCC4, MRP4), and the hydrolysis of released cAMP to AMP by ENPP2, followed by dephosphorylation to adenosine again by CD73 and putatively, TNAP [114]. The third contribution is based on a synthesis pathway, where cADPR, generated by the enzyme ecto-NAD-glycohydrolase (CD38, ADP-ribosyl cyclase 1) via NAD + , can be converted to AMP (by ENPP1) to then be dephosphorylated to adenosine by CD73 and again, putatively, TNAP [112,113].…”

Section: The Molecular Role Of Tnap In Inflammation Processesmentioning

confidence: 99%

TNAP as a New Player in Chronic Inflammatory Conditions and Metabolism

Graser

Liedtke

Jakob

2021

IJMS

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This review summarizes important information on the ectoenzyme tissue-nonspecific alkaline phosphatase (TNAP) and gives a brief insight into the symptoms, diagnostics, and treatment of the rare disease Hypophosphatasia (HPP), which is resulting from mutations in the TNAP encoding ALPL gene. We emphasize the role of TNAP beyond its well-known contribution to mineralization processes. Therefore, above all, the impact of the enzyme on central molecular processes in the nervous system and on inflammation is presented here.

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Activation of Adenylyl Cyclase Causes Stimulation of Adenosine Receptors

Cited by 24 publications

References 53 publications

ATP and Its Metabolite Adenosine as Regulators of Dendritic Cell Activity

ATP and Its Metabolite Adenosine as Regulators of Dendritic Cell Activity

Extracellular Adenosine (eAdo) - A2B Receptor Axis Inhibits in Nlrp3 Inflammasome-dependent Manner Trafficking of Hematopoietic Stem/progenitor Cells

TNAP as a New Player in Chronic Inflammatory Conditions and Metabolism

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