scholarly journals Extracellular Nucleotides Regulate Arterial Calcification by Activating Both Independent and Dependent Purinergic Receptor Signaling Pathways

2020 ◽  
Vol 21 (20) ◽  
pp. 7636 ◽  
Author(s):  
Britt Opdebeeck ◽  
Isabel R. Orriss ◽  
Ellen Neven ◽  
Patrick C. D’Haese ◽  
Anja Verhulst
Keyword(s):  
Purinergic Receptors ◽  
Molecular Mechanisms ◽  
Purinergic Receptor ◽  
Bone Mineralization ◽  
Purinergic Signaling ◽  
Extracellular Nucleotides ◽  
Arterial Calcification ◽  
Nucleoside Triphosphate ◽  
Vascular Cells ◽  
Bone Homeostasis

Arterial calcification, the deposition of calcium-phosphate crystals in the extracellular matrix, resembles physiological bone mineralization. It is well-known that extracellular nucleotides regulate bone homeostasis raising an emerging interest in the role of these molecules on arterial calcification. The purinergic independent pathway involves the enzymes ecto-nucleotide pyrophosphatase/phosphodiesterases (NPPs), ecto-nucleoside triphosphate diphosphohydrolases (NTPDases), 5′-nucleotidase and alkaline phosphatase. These regulate the production and breakdown of the calcification inhibitor—pyrophosphate and the calcification stimulator—inorganic phosphate, from extracellular nucleotides. Maintaining ecto-nucleotidase activities in a well-defined range is indispensable as enzymatic hyper- and hypo-expression has been linked to arterial calcification. The purinergic signaling dependent pathway focusses on the activation of purinergic receptors (P1, P2X and P2Y) by extracellular nucleotides. These receptors influence arterial calcification by interfering with the key molecular mechanisms underlying this pathology, including the osteogenic switch and apoptosis of vascular cells and possibly, by favoring the phenotypic switch of vascular cells towards an adipogenic phenotype, a recent, novel hypothesis explaining the systemic prevention of arterial calcification. Selective compounds influencing the activity of ecto-nucleotidases and purinergic receptors, have recently been developed to treat arterial calcification. However, adverse side-effects on bone mineralization are possible as these compounds reasonably could interfere with physiological bone mineralization.

Abstract 353: P2Y 2 Nucleotide Receptor Overexpression: Letting Blind Cardiac Progenitor Cells ‘See’ Again

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Farid Khalafalla ◽  
Steven Greene ◽  
Jonathan Nguyen ◽  
Kelli Ilves ◽  
Benjamin Norman ◽  
...  
Keyword(s):  
Stem Cells ◽  
Progenitor Cells ◽  
Purinergic Receptors ◽  
Molecular Mechanisms ◽  
Purinergic Signaling ◽  
Healing Process ◽  
Extracellular Nucleotides ◽  
Functional Responses ◽  
And Migration ◽  
Proliferation And Migration

Heart failure (HF) is a leading cause of death in the US due to limited capability of adult mammalian heart to regenerate after myocardial infarction (MI). Autologous stem cell therapy holds promise for promoting regeneration of injured heart but stem cells derived from diseased organs exhibit poor proliferative, migratory and survival capabilities. Empowering cardiac-derived progenitor cells (CPC) with prosurvival genes has been attempted. However, molecular mechanisms by which stem cells detect stress signals to subsequently initiate appropriate regenerative responses are poorly understood. In this regard, purinergic receptors represent a major detector for extracellular nucleotides released during injury/stress and serve as an intracellular platform harboring numerous signaling pathways that regulate proinflammatory and regenerative responses required for the healing process. Despite the established roles of purinergic signaling in cardiovascular diseases, it has not been well-defined in CPCs. This study shows, for the first time, that the majority of P2 purinergic receptors are expressed and exhibit functional responses to ATP and UTP in human CPCs (hCPC) isolated from HF patients. The G protein-coupled P2Y 2 R is a pivotal stress detector that senses ATP and UTP accumulated in extracellular space after injury and mediates regenerative responses in various injury models, including MI model, and in stem cells from diverse origins. Interestingly, hCPCs with relatively slower growth kinetics and enhanced senescence show dramatic decreases in P2Y 2 receptor (P2Y 2 R) expression compared to fast-growing hCPCs, consistent with our hypothesis that overexpressing P2Y 2 R enables diseased hCPCs to better detect stress stimuli and react with the proper regenerative responses. Along this line, P2Y 2 R stimulation with UTP enhances hCPC proliferation and migration. Interestingly, preliminary results demonstrate that UTP treatment induces YAP activation and nuclear shuttling. Moreover, inhibition of YAP/TEAD interaction impairs UTP-induced proliferation and migration revealing a novel link between extracellular nucleotides released during cardiac ischemia and Hippo signaling that has been recently implicated in cardiac regeneration.

scholarly journals Gq-coupled Purinergic Receptors Inhibit Insulin-like Growth Factor-I/Phosphoinositide 3-Kinase Pathway-dependent Keratinocyte Migration

2010 ◽  
Vol 21 (6) ◽  
pp. 946-955 ◽  
Author(s):  
Salma Taboubi ◽  
Françoise Garrouste ◽  
Fabrice Parat ◽  
Gilbert Pommier ◽  
Emilie Faure ◽  
...  
Keyword(s):  
Growth Factor ◽  
Purinergic Receptors ◽  
Purinergic Signaling ◽  
Extracellular Nucleotides ◽  
Dependent Manner ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Keratinocyte Migration ◽  
Igf I ◽  
Growth Factor I

Insulin-like growth factor-I (IGF-I) activation of phosphoinositol 3-kinase (PI3K) is an essential pathway for keratinocyte migration that is required for epidermis wound healing. We have previously reported that activation of Gα(q/11)-coupled-P2Y2purinergic receptors by extracellular nucleotides delays keratinocyte wound closure. Here, we report that activation of P2Y2receptors by extracellular UTP inhibits the IGF-I–induced p110α-PI3K activation. Using siRNA and pharmacological inhibitors, we demonstrate that the UTP antagonistic effects on PI3K pathway are mediated by Gα(q/11)—and not G(i/o)—independently of phospholipase Cβ. Purinergic signaling does not affect the formation of the IGF-I receptor/insulin receptor substrate-I/p85 complex, but blocks the activity of a membrane-targeted active p110α mutant, indicating that UTP acts downstream of PI3K membrane recruitment. UTP was also found to efficiently attenuate, within few minutes, the IGF-I–induced PI3K-controlled translocation of the actin-nucleating protein cortactin to the plasma membrane. This supports the UTP ability to alter later migratory events. Indeed, UTP inhibits keratinocyte spreading and migration promoted by either IGF-I or a membrane-targeted active p110α mutant, in a Gα(q/11)-dependent manner both. These findings provide new insight into the signaling cross-talk between receptor tyrosine kinase and Gα(q/11)-coupled receptors, which mediate opposite effects on p110α-PI3K activity and keratinocyte migration.

scholarly journals Extracellular nucleotides inhibit oxalate transport by human intestinal Caco-2-BBe cells through PKC-δ activation

2013 ◽  
Vol 305 (1) ◽  
pp. C78-C89 ◽  
Author(s):  
Ruhul Amin ◽  
Sapna Sharma ◽  
Sireesha Ratakonda ◽  
Hatim A. Hassan
Keyword(s):  
Calcium Oxalate ◽  
Purinergic Receptor ◽  
Purinergic Signaling ◽  
Stone Formation ◽  
Surface Expression ◽  
Extracellular Nucleotides ◽  
Major Health Problem ◽  
Oxalate Secretion ◽  
Inflammatory Bowel ◽  
Oxalate Transport

Nephrolithiasis remains a major health problem in Western countries. Seventy to 80% of kidney stones are composed of calcium oxalate, and small changes in urinary oxalate affect risk of kidney stone formation. Intestinal oxalate secretion mediated by the anion exchanger SLC26A6 plays an essential role in preventing hyperoxaluria and calcium oxalate nephrolithiasis, indicating that understanding the mechanisms regulating intestinal oxalate transport is critical for management of hyperoxaluria. Purinergic signaling modulates several intestinal processes through pathways including PKC activation, which we previously found to inhibit Slc26a6 activity in mouse duodenal tissue. We therefore examined whether purinergic stimulation with ATP and UTP affects oxalate transport by human intestinal Caco-2-BBe (C2) cells. We measured [14C]oxalate uptake in the presence of an outward Cl−gradient as an assay of Cl−/oxalate exchange activity, ≥50% of which is mediated by SLC26A6. We found that ATP and UTP significantly inhibited oxalate transport by C2 cells, an effect blocked by the PKC inhibitor Gö-6983. Utilizing pharmacological agonists and antagonists, as well as PKC-δ knockdown studies, we observed that ATP inhibits oxalate transport through the P2Y2receptor, PLC, and PKC-δ. Biotinylation studies showed that ATP inhibits oxalate transport by lowering SLC26A6 surface expression. These findings are of potential relevance to pathophysiology of inflammatory bowel disease-associated hyperoxaluria, where supraphysiological levels of ATP/UTP are expected and overexpression of the P2Y2receptor has been reported. We conclude that ATP and UTP inhibit oxalate transport by lowering SLC26A6 surface expression in C2 cells through signaling pathways including the P2Y2purinergic receptor, PLC, and PKC-δ.

scholarly journals P2X7 Receptor as a Key Player in Oxidative Stress-Driven Cell Fate in Nonalcoholic Steatohepatitis

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Saurabh Chatterjee ◽  
Suvarthi Das
Keyword(s):  
Oxidative Stress ◽  
Nonalcoholic Steatohepatitis ◽  
Purinergic Receptors ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Purinergic Receptor ◽  
Leptin Resistance ◽  
Hepatocellular Injury ◽  
Cardiometabolic Disorders

Incidences of nonalcoholic fatty liver disease parallels increase in the global obesity epidemic. NAFLD has been shown to be associated with risks of cardiometabolic disorders and kidney disturbances. It is accompanied by insulin and leptin resistance that complicate the diagnosis and treatment of this public health menace. Though significant research is underway for understanding the molecular mechanisms of NAFLD and its subsequent inflammatory and fibrotic manifestations like nonalcoholic steatohepatitis, the role of purinergic receptors has been unclear. It is increasingly being recognized that damage associated molecular patterns like NAD and ATP that are released from injured cells via hepatocellular injury either by oxidative stress or lipotoxicity from steatosis activate the purinergic receptor. Based on evidence from inflammatory responses in the airways and vasculature and autoimmune complications in humans and rodents, it is beyond doubt that hepatocellular inflammation such as that seen in NASH can result from the activation of purinergic receptors. This event can result in the formation of inflammasomes and can be an important pathway for the progression of NASH. The present review evaluates the current knowledge of the role of oxidative stress and its signaling via P2X7 receptors in hepatocellular injury that might contribute to the NASH pathophysiology.

scholarly journals Possible Effects of Microbial Ecto-Nucleoside Triphosphate Diphosphohydrolases on Host-Pathogen Interactions

2008 ◽  
Vol 72 (4) ◽  
pp. 765-781 ◽  
Author(s):  
Fiona M. Sansom ◽  
Simon C. Robson ◽  
Elizabeth L. Hartland
Keyword(s):  
Legionella Pneumophila ◽  
Purinergic Signaling ◽  
Extracellular Nucleotides ◽  
Microbial Pathogens ◽  
Nucleoside Triphosphate ◽  
Host Pathogen Interactions ◽  
Host Pathogen ◽  
Specific Receptors ◽  
Parasitic Pathogens

SUMMARYIn humans, purinergic signaling plays an important role in the modulation of immune responses through specific receptors that recognize nucleoside tri- and diphosphates as signaling molecules. Ecto-nucleoside triphosphate diphosphohydrolases (ecto-NTPDases) have important roles in the regulation of purinergic signaling by controlling levels of extracellular nucleotides. This process is key to pathophysiological protective responses such as hemostasis and inflammation. Ecto-NTPDases are found in all higher eukaryotes, and recently it has become apparent that a number of important parasitic pathogens of humans express surface-located NTPDases that have been linked to virulence. For those parasites that are purine auxotrophs, these enzymes may play an important role in purine scavenging, although they may also influence the host response to infection. Although ecto-NTPDases are rare in bacteria, expression of a secreted NTPDase in Legionella pneumophila was recently described. This ecto-enzyme enhances intracellular growth of the bacterium and potentially affects virulence. This discovery represents an important advance in the understanding of the contribution of other microbial NTPDases to host-pathogen interactions. Here we review other progress made to date in the characterization of ecto-NTPDases from microbial pathogens, how they differ from mammalian enzymes, and their association with organism viability and virulence. In addition, we postulate how ecto-NTPDases may contribute to the host-pathogen interaction by reviewing the effect of selected microbial pathogens on purinergic signaling. Finally, we raise the possibility of targeting ecto-NTPDases in the development of novel anti-infective agents based on potential structural and clear enzymatic differences from the mammalian ecto-NTPDases.

scholarly journals Purinergic Receptors: Elucidating the Role of These Immune Mediators in HIV-1 Fusion

2020 ◽  
Author(s):  
Tracey L. Freeman ◽  
Talia H. Swartz
Keyword(s):  
Membrane Fusion ◽  
Purinergic Receptors ◽  
Purinergic Receptor ◽  
Extracellular Nucleotides ◽  
Viral Membrane ◽  
Immune Mediators ◽  
Receptor Interactions ◽  
Viral Membrane Fusion ◽  
Hiv 1

Purinergic receptors are inflammatory mediators activated by extracellular nucleotides released by dying or injured cells. Several studies have described an important role for these receptors in HIV-1 entry, particularly regarding their activity on HIV-1 viral membrane fusion. Several reports identify purinergic receptor antagonists that inhibit HIV-1 membrane fusion; these drugs are suspected to act through antagonizing Env-chemokine receptor interactions. They also appear to abrogate activity of downstream mediators that potentiate activation of the NLRP3 inflammasome pathway. Here we review the literature on purinergic receptors, the drugs that inhibit their function, and the evidence implicating these receptors in HIV-1 entry.

scholarly journals Purinergic Receptors: Elucidating the Role of these Immune Mediators in HIV-1 Fusion

Viruses ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 290
Author(s):  
Tracey L. Freeman ◽  
Talia H. Swartz
Keyword(s):  
Membrane Fusion ◽  
Purinergic Receptors ◽  
Purinergic Receptor ◽  
Extracellular Nucleotides ◽  
Viral Membrane ◽  
Immune Mediators ◽  
Receptor Interactions ◽  
Viral Membrane Fusion ◽  
Hiv 1

Purinergic receptors are inflammatory mediators activated by extracellular nucleotides released by dying or injured cells. Several studies have described an important role for these receptors in HIV-1 entry, particularly regarding their activity on HIV-1 viral membrane fusion. Several reports identify purinergic receptor antagonists that inhibit HIV-1 membrane fusion; these drugs are suspected to act through antagonizing Env-chemokine receptor interactions. They also appear to abrogate activity of downstream mediators that potentiate activation of the NLRP3 inflammasome pathway. Here we review the literature on purinergic receptors, the drugs that inhibit their function, and the evidence implicating these receptors in HIV-1 entry.

Abstract 25: P2Y14 Purinergic Receptor Overexpression: Letting Blind Cardiac Progenitor Cells ’See’ Again

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Farid G Khalafalla ◽  
Waqas Kayani ◽  
Arwa Kassab ◽  
Kelli Ilves ◽  
Roberto J Alvarez ◽  
...  
Keyword(s):  
Stem Cells ◽  
Progenitor Cells ◽  
Molecular Mechanisms ◽  
Purinergic Receptor ◽  
Extracellular Nucleotides ◽  
Cardiac Progenitor Cells ◽  
Regenerative Capacity ◽  
Paracrine Factors ◽  
Poor Growth ◽  
Hematopoietic Stem

Heart failure (HF) is a leading cause of death due to limited regenerative capacity of adult mammalian heart following injury. Autologous stem cell therapy holds promise for promoting cardiac regeneration. However, stem cells derived from aged/diseased organs exhibit poor growth and survival capabilities. Empowering cardiac progenitor cells (CPC) with prosurvival genes has been attempted. Nonetheless, the molecular mechanisms by which stem cells initially detect stress signals to stimulate appropriate regenerative responses are poorly understood. This study aims to explore the physiological responses mediated by purinergic receptors, which represent a major detector for extracellular nucleotides released during injury/stress, with a focus on P2Y 14 nucleotide receptor (P2Y 14 R) activated by extracellular UDP-conjugated sugars. P2Y 14 R mediates proliferation of keratinocytes and chemotaxis of neutrophils and hematopoietic stem cells (HSCs). In addition, P2Y 14 R enhances HSC resistance to stress-induced senescence and maintains regenerative capacity after injury. However, the physiological roles of P2Y 14 R in CPCs are largely unknown. Preliminary data show striking correlations between P2Y 14 R expression in human CPCs derived from HF patients (hCPCs) and patients’ ejection fraction (EF), where low EF corresponds to low P2Y 14 R expression hCPCs. Moreover, hCPCs with relatively slower growth kinetics and enhanced senescence exhibit dramatic decreases in P2Y 14 R expression compared to fast-growing hCPCs. P2Y 14 R overexpression improves hCPC proliferation, migration, survival under stress stimuli and reverses senescent-associated phenotypes. Furthermore, P2Y 14 R-overexpressing hCPCs show remarkable upregulation in the expression of paracrine factors critical for cardiac repair. Preliminary studies will be extended in vivo to assess whether P2Y 14 R overexpression in hCPCs improves their reparative potential for injured mouse myocardium. Overall, this study introduces a novel interventional molecular approach to improve the therapeutic outcome of hCPCs by enhancing their capability to detect stress-induced extracellular nucleotides and initiate proper regenerative responses through augmenting P2Y 14 R expression.

scholarly journals Purinergic regulation: From a risky hypothesis to a triumphant theory

2021 ◽  
Vol 16 (3) ◽  
pp. 190-202
Author(s):  
Mohammad Kamran Sarkandi ◽  
◽  
Natalia Serebryanaya ◽  
◽  
Keyword(s):  
Functional State ◽  
Purinergic Receptors ◽  
Purinergic Signaling ◽  
Signal Transmission ◽  
The Body ◽  
Extracellular Nucleotides ◽  
Receptor Interaction ◽  
First Time

With the discovery of the ATP structure in 1929, significant progress was made in understanding the role of nucleosides and nucleotides in the body. One of the most important breakthroughs is associated with the determination of the function of an autacoid in ATP, a participant in purinergic signal transmission. For the first time, this function of ATP was pointed out by Professor Geoffrey Burnstock in 1972. Purinergic signaling activators are extracellular nucleotides including ATP, ADP, UTP, UDP, and adenosine nucleoside. The purinergic signaling pathway begins with the synthesis and intracellular accumulation of nucleotides, and then their release from the cell under various physiological and pathological conditions. In the extracellular spaces, nucleotides are hydrolyzed by various enzymes with the removal of phosphate groups, which leads to the appearance of various regulatory molecules that interact with P1 and P2 purinergic receptors. This ligand-receptor interaction changes the functional state of the target cell. In turn, the expression of purinergic receptors changes depending on the functional state of the cell. The participation of purinergic regulation in the development of many diseases indicates that by changing the concentration of signaling molecules, it is possible to change the course of pathological processes, in particular the activity of inflammation and the direction of immune responses. This article provides a brief review of the literature on the structure of nucleotide and nucleoside autacoids, enzymes involved in their metabolism, specific purinergic receptors.

scholarly journals Pro- and anti-inflammatory macrophages express a sub-type specific purinergic receptor profile

2021 ◽  
Author(s):  
J. Merz ◽  
A. Nettesheim ◽  
S. von Garlen ◽  
P. Albrecht ◽  
B. S. Saller ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Purinergic Receptors ◽  
Purinergic Receptor ◽  
Receptor Activation ◽  
Extracellular Nucleotides ◽  
M1 Macrophages ◽  
Murine Bone Marrow ◽  
Receptor Profile ◽  
Anti Inflammatory

AbstractExtracellular nucleotides act as danger signals that orchestrate inflammation by purinergic receptor activation. The expression pattern of different purinergic receptors may correlate with a pro- or anti-inflammatory phenotype. Macrophages function as pro-inflammatory M1 macrophages (M1) or anti-inflammatory M2 macrophages (M2). The present study found that murine bone marrow-derived macrophages express a unique purinergic receptor profile during in vitro polarization. As assessed by real-time polymerase chain reaction (PCR), Gαs-coupled P1 receptors A2A and A2B are upregulated in M1 and M2 compared to M0, but A2A 15 times higher in M1. The ionotropic P2 receptor P2X5 is selectively upregulated in M1- and M2-polarized macrophages. P2X7 is temporarily expressed in M1 macrophages. Metabotropic P2Y receptors showed a distinct expression profile in M1 and M2-polarized macrophages: Gαq coupled P2Y1 and P2Y6 are exclusively upregulated in M2, whereas Gαi P2Y13 and P2Y14 are overexpressed in M1. This consequently leads to functional differences between M1 and M2 in response to adenosine di-phosphate stimulation (ADP): In contrast to M1, M2 showed increased cytoplasmatic calcium after ADP stimulation. In the present study we show that bone marrow-derived macrophages express a unique repertoire of purinergic receptors. We show for the first time that the repertoire of purinergic receptors is highly flexible and quickly adapts upon pro- and anti-inflammatory macrophage differentiation with functional consequences to nucleotide stimulation.

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