Academic literature on the topic 'Adenine nucleotides Receptors'
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Journal articles on the topic "Adenine nucleotides Receptors"
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Stone, Trevor W. "Receptors for adenosine and adenine nucleotides." General Pharmacology: The Vascular System 22, no. 1 (January 1991): 25–31. http://dx.doi.org/10.1016/0306-3623(91)90305-p.
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Newman, George C., Frank E. Hospod, Sean D. Trowbridge, Shilpa Motwani, and Yan Liu. "Restoring Adenine Nucleotides in a Brain Slice Model of Cerebral Reperfusion." Journal of Cerebral Blood Flow & Metabolism 18, no. 6 (June 1998): 675–85. http://dx.doi.org/10.1097/00004647-199806000-00010.
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Tissue adenine nucleotides are depleted during cerebral ischemia, impeding recovery after reperfusion. Although prior studies have attempted to prevent the initial loss of adenylates, the present study tests the hypothesis that stimulating synthesis of adenine nucleotides, through either adenosine kinase or adenine phosphoribosyltransferase, would result in significant cerebroprotection. To study the effects on neurons and glia directly while avoiding the influence of the cerebral vasculature, hippocampal brain slices were used for the model of transient ischemia with reperfusion. The standard brain slice insult of brief exposure to anoxia with aglycemia was modified based on studies which showed that a 30-minute exposure to air with 1 mmol/L glucose produced a stable, moderate reduction in ATP during the insult and that, 2 hours after return to normal conditions, there was moderate depletion of tissue adenine nucleotides and histologic injury. Treatments with 1 mmol/L adenosine, AMP, or adenine were equivalent in partially re-storing adenine nucleotides. Despite this, only adenosine af-forded histologic protection, suggesting a protective role for adenosine receptors. There also was evidence for metabolic cycling among adenine nucleotides, nucleosides, and purines. Adenosine may exert direct cerebroprotective effects on neural tissue as well as indirect effects through the cerebral vasculature.
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Gorman, Mark W., Kayoko Ogimoto, Margaret V. Savage, Kenneth A. Jacobson, and Eric O. Feigl. "Nucleotide coronary vasodilation in guinea pig hearts." American Journal of Physiology-Heart and Circulatory Physiology 285, no. 3 (September 2003): H1040—H1047. http://dx.doi.org/10.1152/ajpheart.00981.2002.
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The role of P1 receptors and P2Y1 receptors in coronary vasodilator responses to adenine nucleotides was examined in the isolated guinea pig heart. Bolus arterial injections of nucleotides were made in hearts perfused at constant pressure. Peak increase in flow was measured before and after addition of purinoceptor antagonists. Both the P1 receptor antagonist 8-( p-sulfophenyl)theophylline and adenosine deaminase inhibited adenosine vasodilation. AMP-induced vasodilation was inhibited by P1 receptor blockade but not by adenosine deaminase or by the selective P2Y1 antagonist N6-methyl-2′-deoxyadenosine 3′,5′-bisphosphate (MRS 2179). ADP-induced vasodilation was moderately inhibited by P1 receptor blockade and greatly inhibited by combined P1 and P2Y1 blockade. ATP-induced vasodilation was antagonized by P1 blockade but not by adenosine deaminase. Addition of P2Y1 blockade to P1 blockade shifted the ATP dose-response curve further rightward. It is concluded that in this preparation ATP-induced vasodilation results primarily from AMP stimulation of P1 receptors, with a smaller component from ATP or ADP acting on P2Y1 receptors. ADP-induced vasodilation is largely due to P2Y1 receptors, with a smaller contribution by AMP or adenosine acting via P1 receptors. AMP responses are mediated solely by P1 receptors. Adenosine contributes very little to vasodilation resulting from bolus intracoronary injections of ATP, ADP, or AMP.
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Murugappan, Swaminathan, Haripriya Shankar, and Satya P. Kunapuli. "Platelet Receptors for Adenine Nucleotides and Thromboxane A2." Seminars in Thrombosis and Hemostasis 30, no. 4 (August 2004): 411–18. http://dx.doi.org/10.1055/s-2004-833476.
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Eltzschig, Holger K., Linda F. Thompson, Jorn Karhausen, Richard J. Cotta, Juan C. Ibla, Simon C. Robson, and Sean P. Colgan. "Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism." Blood 104, no. 13 (December 15, 2004): 3986–92. http://dx.doi.org/10.1182/blood-2004-06-2066.
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Abstract Hypoxia is a well-documented inflammatory stimulus and results in tissue polymorphonuclear leukocyte (PMN) accumulation. Likewise, increased tissue adenosine levels are commonly associated with hypoxia, and given the anti-inflammatory properties of adenosine, we hypothesized that adenosine production via adenine nucleotide metabolism at the vascular surface triggers an endogenous anti-inflammatory response during hypoxia. Initial in vitro studies indicated that endogenously generated adenosine, through activation of PMN adenosine A2A and A2B receptors, functions as an antiadhesive signal for PMN binding to microvascular endothelia. Intravascular nucleotides released by inflammatory cells undergo phosphohydrolysis via hypoxia-induced CD39 ectoapyrase (CD39 converts adenosine triphosphate/adenosine diphosphate [ATP/ADP] to adenosine monophosphate [AMP]) and CD73 ecto-5′-nucleotidase (CD73 converts AMP to adenosine). Extensions of our in vitro findings using cd39- and cd73-null animals revealed that extracellular adenosine produced through adenine nucleotide metabolism during hypoxia is a potent anti-inflammatory signal for PMNs in vivo. These findings identify CD39 and CD73 as critical control points for endogenous adenosine generation and implicate this pathway as an innate mechanism to attenuate excessive tissue PMN accumulation. (Blood. 2004;104:3986-3992)
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Williams, Wynford R. "Dampening of neurotransmitter action: molecular similarity within the melatonin structure." Endocrine Regulations 52, no. 4 (October 1, 2018): 199–207. http://dx.doi.org/10.2478/enr-2018-0025.
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AbstractObjectives. Melatonin initiates physiologic and therapeutic responses in various tissues through binding to poorly defined MT receptors regulated by G-proteins and purine nucleotides. Melatonin’s interaction with other G-protein regulated receptors, including those of serotonin, is unclear. This study explores the potential for the interaction of melatonin with nucleotide and receptor ligand structures. Methods. The study uses a computational program to investigate relative molecular similarity by the comparative superimposition and quantitative fitting of molecular structures to adenine and guanine nucleotide templates. Results. A minimum energy melatonin conformer replicates the nucleotide fits of ligand structures that regulate Gαi and Gαq proteins via serotonin, dopamine, opioid, α-adrenoceptor, and muscarinic receptor classes. The same conformer also replicates the nucleotide fits of ligand structures regulating K+ and Ca2+ ion channels. The acyl-methoxy distance within the melatonin conformer matches a carbonyl-hydroxyl distance in guanine nucleotide. Conclusion. Molecular similarity within the melatonin and ligand structures relates to the established effects of melatonin on cell receptors regulated by purine nucleotides in cell signal transduction processes. Pharmacologic receptor promiscuity may contribute to the widespread effects of melatonin.
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Antos, Laura K., and Lincoln R. Potter. "Adenine nucleotides decrease the apparentKmof endogenous natriuretic peptide receptors for GTP." American Journal of Physiology-Endocrinology and Metabolism 293, no. 6 (December 2007): E1756—E1763. http://dx.doi.org/10.1152/ajpendo.00321.2007.
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Natriuretic peptide receptors A (NPR-A) and B (NPR-B) mediate most effects of natriuretic peptides by synthesizing cGMP. ATP increases the activity of these receptors by an unknown mechanism. We recently reported that a nonhydrolyzable form of ATP, adenylyl imidodiphosphate (AMPPNP), stabilizes but is not required for the activation of NPR-A and NPR-B in membranes from highly overexpressing cells. Here, we repeated these studies on receptors expressed in endogenous settings. Kinetic analysis indicated that both AMPPNP and ATP dramatically decrease the apparent Kmof both receptors for GTP but had little effect on the Vmax. The EC50for AMPPNP decreased as substrate concentration increased whereas the magnitude of the effect was greater at lower GTP concentrations. ATP increased the activity of a mutant receptor containing glutamates substituted for all known phosphorylation sites similarly to the wild-type receptor, consistent with a phosphorylation independent mechanism. Finally, the putative ATP binding sites were investigated. Mutation of the ATP modulatory domain region had no effect, but mutation of K535A dramatically diminished ANP-dependent cyclase activity in a manner that was unresponsive to ATP. Mutation of the highly conserved 630-KSS to AAA (all alanines) resulted in an expressed receptor that had no detectable guanylyl cyclase activity. We conclude that ATP is not required for the initial activation of NPRs but does increase activity over time by reducing the apparent Kmfor GTP.
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Kawa, Kazuyoshi. "Discrete but simultaneous release of adenine nucleotides and serotonin from mouse megakaryocytes as detected with patch- and carbon-fiber electrodes." American Journal of Physiology-Cell Physiology 286, no. 1 (January 2004): C119—C128. http://dx.doi.org/10.1152/ajpcell.00014.2003.
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Using patch- and carbon-fiber electrodes, we studied release phenomena of adenine nucleotides and serotonin from megakaryocytes isolated from the bone marrow of the mouse. Megakaryocytes express ionotropic purinergic receptors on their surfaces. Under the condition of whole cell recording, the cells showed spikelike spontaneous inward currents. The spontaneous currents were carried by cations and had amplitudes of 30–800 pA at –43 mV and durations of 0.1–0.3 s. Pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS; 100 μM) and suramin (100 μM), purinoceptor-blocking agents, depressed the currents reversibly. It is thought that the receptor involved was the P2X1 subtype on the cell and that the currents were due to activation of the P2X1 receptor by adenine nucleotides released from the cell. The currents showed a skewed amplitude distribution, suggesting variation of vesicular contents and/or distinct localization or varied density of receptors on the cell. Frequency of the spontaneous inward currents was enhanced by external application of platelet-activating substances, thrombin (0.4 U/ml), phorbol ester (100 nM), and ADP (2 μM), at low concentrations. With a carbon-fiber electrode, which can detect oxidizable substances including serotonin, spikelike oxidation currents from the external surface of the megakaryocyte were detected. The frequency of the oxidation currents increased remarkably after the application of thrombin (10 U/ml). The majority of the oxidation currents coincided with the rising phase of the whole cell currents, suggesting corelease of serotonin and adenine nucleotide from the same vesicle. We concluded that megakaryocytes store adenine nucleotides and serotonin in the same vesicle and release them simultaneously in a discrete manner.
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Puchałowicz, Kamila, Maciej Tarnowski, Marta Tkacz, Dariusz Chlubek, Patrycja Kłos, and Violetta Dziedziejko. "Extracellular Adenine Nucleotides and Adenosine Modulate the Growth and Survival of THP-1 Leukemia Cells." International Journal of Molecular Sciences 21, no. 12 (June 22, 2020): 4425. http://dx.doi.org/10.3390/ijms21124425.
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A new approach to improve the effectiveness of acute myeloid leukemia (AML) treatment is to use the properties of purinergic signaling molecules secreted into the bone marrow milieu in response to leukemic cell growth. Therefore, our study aimed to evaluate the effects of extracellular adenine nucleotides and adenosine on the growth and death parameters in the leukemic THP-1 cell line. Cells were exposed to ATP, ADP, AMP, adenosine and nonhydrolyzable analogues of ATP and ADP (ATPγS and ADPβS) in a 1–1000 μM broad concentration range. The basal mRNA expression of the P1 and P2 receptors was evaluated by real-time PCR. Changes in the processes of cell growth and death were assessed by flow cytometry analysis of proliferation, cell cycle and apoptosis. Chemotaxis toward stromal cell-derived factor-1 (SDF-1) was performed using the modified Boyden chamber assay, and chemokine receptor type 4 (CXCR4) surface expression was quantified by flow cytometry. We indicated several antileukemic actions. High micromolar concentrations (100–1000 μM) of extracellular adenine nucleotides and adenosine inhibit the growth of cells by arresting the cell cycle and/or inducing apoptosis. ATP is characterized by the highest potency and widest range of effects, and is responsible for the cell cycle arrest and the apoptosis induction. Compared to ATP, the effect of ADP is slightly weaker. Adenosine mostly has a cytotoxic effect, with the induction of apoptosis. The last studied nucleotide, AMP, demonstrated only a weak cytotoxic effect without affecting the cell cycle. In addition, cell migration towards SDF-1 was inhibited by low micromolar concentrations (10 μM). One of the reasons for this action of ATPγS and adenosine was a reduction in CXCR4 surface expression, but this only partially explains the mechanism of antimigratory action. In summary, extracellular adenine nucleotides and adenosine inhibit THP-1 cell growth, cause death of cells and modulate the functioning of the SDF-1/CXCR4 axis. Thus, they negatively affect the processes that are responsible for the progression of AML and the difficulties in AML treatment.
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Cattaneo, M. "The platelet P2 receptors in inflammation." Hämostaseologie 35, no. 03 (2015): 262–66. http://dx.doi.org/10.5482/hamo-14-09-0044.
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SummaryIn addition to their well characterized and established role in haemostasis and thrombosis, platelets contribute to the pathogenesis of inflammation. Adenine nucleotides are signalling molecules that regulate the function of virtually every cell in the body, by interacting with P2 receptors. Their important role in inflammation is well established. In the last few years, the pro-inflammatory roles of adenine nucleotides interacting with their platelet P2 receptors has emerged. In particular, it was shown that the platelet P2Y12 receptor for ADP significantly contributed to the proinflammatory effects of cysteinyl leukotrienes (CysLT) in experimental models of asthma in mice. More importantly, it was recently shown that P2Y12 variants were associated with lung function in a large family-based asthma cohort and that the P2Y12 antagonist prasugrel tended to decrease bronchial hyper-reactivity to mannitol in patients with allergic bronchial asthma in a randomized, placebo controlled trial.These data strongly suggest that P2Y12 may represent an important pharmacological target for the treatment of patients with allergic bronchial asthma.
Dissertations / Theses on the topic "Adenine nucleotides Receptors"
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Crisp, Michael G. "Organoplatinum(II) complexes with hydrogen-bonding functionality and their potential use as molecular receptors for adenine : a thesis submitted for the degree of Master of Science." Title page, abstract and contents only, 2002. http://web4.library.adelaide.edu.au/theses/09SM/09smc932.pdf.
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Errata pasted onto front end-paper. Includes bibliographical references (leaves 82-86). Describes the preparation and characterisation of a novel series of organoplatinum(II) complexes with hydrogen-bonding functionality.
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Gaboardi, Angela Kampfer. "Regulation of the cardiac isoform of the ryanodine receptor by S-adenosyl-l-methionine." Diss., Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/42854.
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Activity of the Ryanodine Receptor (RyR2) (aka cardiac Ca2+ release channel) plays a pivotal role in contraction of the heart. S-adenosyl-l-methionine (SAM) is a biological methyl group donor that has close structural similarity to ATP, an important physiological regulator of RyR2. This work provides evidence that SAM can act as a RyR2 regulatory ligand in a manner independent from its recognized role as a biological methyl group donor. RyR2 activation appears to arise from the direct interaction of SAM, via its adenosyl moiety, with the RyR2 adenine nucleotide binding sites. Because uncertainty remains regarding the structural motifs involved in RyR2 modulation by ATP and its metabolites, this finding has important implications for clarifying the structural basis of ATP regulation of RyR2.
During the course of this project, direct measurements of single RyR2 activity revealed that SAM has distinct effects on RyR2 conductance. From the cytosolic side of the channel, SAM produced a single clearly resolved subconductance state. The effects of SAM on channel conductance were dependent on SAM concentration and membrane holding potential. A second goal of this work was to distinguish between the two possible mechanisms by which SAM could reduce RyR2 conductance: i) SAM interfering directly with ion permeation via binding within the conduction pathway (pore block), or ii) SAM binding a regulatory (or allosteric) site thereby stabilizing or inducing a reduced conductance conformation of the channel. It was determined that SAM does not directly interact with the RyR2 conduction pathway.
To account for these observations an allosteric model for the effect of SAM on RyR2 conductance is proposed. According to this model, SAM binding stabilizes an inherent RyR2 subconductance conformation. The voltage dependence of the SAM related subconductance state is accounted for by direct effects of voltage on channel conformation which indirectly alter the affinity of RyR2 for SAM. Patterns in the transitions between RyR2 conductance states in the presence of SAM may provide insight into the structure-activity relationship of RyR2 which can aid in the development of therapeutic strategies targeting this channel.
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Chan, Wei Mun. "Adenine nucleotide activation of the cardiac ryanodine receptor." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.396214.
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Landon, Linda A. Neighbors. "Salivary gland P2 nucleotide receptors : structure and function studies /." free to MU campus, to others for purchase, 1998. http://wwwlib.umi.com/cr/mo/fullcit?p9904855.
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Kong, Qiongman. "Regulations and functions of P2Y₂ and P2X₇ nucleotide receptors in the central nervous system." Diss., Columbia, Mo. : University of Missouri-Columbia, 2007. http://hdl.handle.net/10355/4847.
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Thesis (Ph.D.)--University of Missouri-Columbia, 2007.The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on March 19, 2009) Vita. Includes bibliographical references.
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Tikh, Eugene I. "Regulation of Contractility by Adenosine A1 and A2A Receptors in the Murine Heart: Role of Protein Phosphatase 2A: A Dissertation." eScholarship@UMMS, 2006. https://escholarship.umassmed.edu/gsbs_diss/130.
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Adenosine is a nucleoside that plays an important role in the regulation of contractility in the heart. Adenosine receptors are G-protein coupled and those implicated in regulation of contractility are presumed to act via modulating the activity of adenylyl cyclase and cAMP content of cardiomyocytes. Adenosine A1 receptors (A1R) reduce the contractile response of the myocardium to β-adrenergic stimulation. This is known as anti adrenergic action. The A2A adenosine receptor (A2AR) has the opposite effect of increasing contractile responsiveness of the myocardium. The A2AR also appears to attenuate the effects of A1R. The effects of these receptors have been primarily studied in the rat heart and with the utilization of cardiomyocyte preparations. With the increasing use of receptor knockout murine models and murine models of various pathological states, it is of importance to comprehensively study the effects of adenosine receptors on regulation of contractility in the murine heart. The following studies examine the adenosinergic regulation of myocardial contractility in isolated murine hearts. In addition, adenosinergic control of contractility is examined in hearts isolated from A2AR knockout animals. Responses to adenosinergic stimulation in murine isolated hearts are found to be comparable to those observed in the rat, with A1R exhibiting an anti adrenergic action and A2AR conversely enhancing contractility. A significant part of the A2AR effect was found to occur via inhibition of the A1R antiadrenergic action. A part of the anti adrenergic action of A1R has previously been shown to be the result of protein phosphatase 2A activation and localization to membranes. Additional experiments in the present study examine the effect of adenosinergic signaling on PP2A in myocardial extracts from wild type and A2AR knockout hearts. A2AR activation was found to decrease the activity of PP2A and enhance localization of the active enzyme to the cytosol; away from its presumed sites of action. In the A2AR knockout the response to A1R activation was enhanced compared with the wild type and basal PP2A activity was reduced. It is concluded that A2AR modulation of PP2A activity may account for the attenuation of the A1R effect by A2AR observed in the contractile studies.
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Pursell, Natalie W. "Hsp90-Mediated Maturation of Kinases and Nuclear Steroid Hormone Receptors: A Dissertation." eScholarship@UMMS, 2011. https://escholarship.umassmed.edu/gsbs_diss/535.
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Among heat shock proteins, Hsp90 is unusual because it is not required for the proper folding of most cellular proteins but rather is disproportionally linked to the activation of signal transduction proteins including over forty kinases and many steroid hormone receptors. Mutated forms of many Hsp90 clients are causative agents in cancer, making Hsp90 a promising pharmacological target. Many small molecular inhibitors have been identified that competitively bind to the ATP binding site of Hsp90, some of which are in clinical trials as anticancer agents. Although the activation of kinase and hormone receptor clients by Hsp90 and its co-chaperones has been extensively studied, the molecular mechanism of client protein activation is poorly understood.
Hsp90 is a dimeric chaperone containing three domains: the N-terminal (N) and middle (M) domains contribute directly to ATP binding and hydrolysis and the C-terminal (C) domain mediates dimerization. At physiological concentration, Hsp90 predominantly forms dimers, but the possibility that full-length monomers might also function in cells has not been tested. In Chapter 3, we used a single-chain strategy to design a full-length Hsp90 monomer (NMCC). The resulting construct was predominantly monomeric at physiological concentration and did not function to support yeast viability as the sole Hsp90. NMCC Hsp90 was also defective at ATP hydrolysis and the activation of kinase and steroid hormone receptor clients in yeast cells. The ability to support yeast growth was rescued by the addition of a coiled-coil dimerization domain, indicating that the parental single-chain construct is functionally defective because it is monomeric.
After finding that a full-length Hsp90 monomer containing only one ATPase site was unable to support yeast viability or activate Hsp90 clients, we set out to further explore the role of ATPase activity in client protein activation. Approximately 10 % of the yeast proteome binds to Hsp90 making it important to study Hsp90 function in the cellular environment where all binding partners are present. In Chapter 4, we observed that co-expression of different Hsp90 subunits in Saccharomyces cerevisiae caused unpredictable synthetic growth defects due to cross-dimerization. We engineered super-stabilized Hsp90 dimers that resisted cross-dimerization with endogenous Hsp90 and alleviated the synthetic growth defect. We utilized these super-stabilized dimers to analyze the ability of ATPase mutant homodimers to activate known Hsp90 client proteins in yeast cells. We found that ATP binding and hydrolysis by Hsp90 are both required for the efficient maturation of the glucocorticoid hormone receptor (GR) and v-src confirming the critical role of ATP hydrolysis in the maturation of steroid hormone receptors and kinases in vivo.
In addition to its role in the activation of signal transduction client proteins, Hsp90 has been shown to suppress the in vitro aggregation of numerous hard-to-fold proteins. In Chapter 5, we examine the role of charge in Hsp90 anti-aggregation activity. The charge on Hsp90 is largely concentrated in two highly acidic regions. We found that deletion of both charge-rich regions dramatically impaired Hsp90 anti-aggregation activity. Addition of an acid-rich region with a distinct amino acid sequence to our double-deleted Hsp90 construct rescued the anti-aggregation activity of Hsp90 indicating that the net charge contributes to its anti-aggregation activity.
The in vitro anti-aggregation activity of Hsp90 studied in Chapter 5 occurs in the absence of ATP. However, all of the biologically important functions of Hsp90 in cells identified to date, including the maturation of kinases and nuclear steroid hormone receptors, clearly require ATP hydrolysis. Why does Hsp90 robustly hinder the aggregation of hard-to-fold proteins without ATP in vitro, but in vivo uses ATP hydrolysis for all of its essential functions? By utilizing separation of function Hsp90 variants (that specifically lack in vitro anti-aggregation activity) we have begun to address this question. We find that anti-aggregation deficient Hsp90 is unable to support yeast growth under stressful conditions, potentially due to reduced cellular expression. Interestingly, the ATP-independent anti-aggregation activity of Hsp90 has no measureable impact on cellular function. Thus, hindering the aggregation of most hard-to- fold proteins by Hsp90 (independent of ATP hydrolysis) does not appear to be important for cell function. These results suggest a cellular model where the Hsp40/60/70 machinery is responsible for hindering the aggregation of most hard-to-fold proteins while Hsp90 assists in the maturation of a select set of clients in an ATP-dependent fashion, potentially aided by its inherent anti-aggregation properties.
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Feliu, Catherine. "Implication des récepteurs P1 et P2 dans la protection des cellules endothéliales au cours de l’hypoxie-reoxygenation Complementary Role of P2 and adenosine receptors in ATP induced-anti-apoptotic effects against hypoxic injury of HUVECs Current knowledge on the role of P2Y receptors in cardioprotection against ischemia-reperfusion Intra-extracellular quantification of nucleotides and adenosine using UHPLCHRMS: improvement of robustness by the use of ascorbic acid in mobile phase Description of the novel cytoprotective action pathways of ticagrelor against hypoxic lesions at the endothelium." Thesis, Reims, 2019. http://www.theses.fr/2019REIMM202.
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Au cours de l’ischémie cardiaque, la lésion est initiée au niveau de l’endothélium, et progresse aux cardiomyocytes environnants. La signalisation purinergique joue un rôle important au cours d’épisodes l’ischémie/reperfusion (I/R). De multiples travaux ont portés sur l’étude des mécanismes de protection des nucléotides et nucléosides, sans pour autant étudier leurs rôles spécifiques sur l’endothélium. Dans ce travail, nous mettons en évidence une augmentation des concentrations extracellulaires en ATP et adénosine provenant de l’endothélium soumis à une hypoxie. Au niveau endothélial, nous mettons en évidence un effet protecteur de l’ATP extracellulaire ainsi qu’un rôle complémentaire des récepteurs P2 et P1. Les récepteurs P2 impliquent les voies de signalisation PI3K, ERK1/2, le canal mKATP et mettent également en jeu la NOS. La protection médiée par les récepteurs P1 implique les voies MEK/ERK1/2, PKA et NOS. Dans un second temps, nous rapportons un nouveau mécanisme cytoprotecteur du ticagrelor, indépendant des éléments figurés du sang et de son effet antiagrégant plaquettaire. Ce mécanisme est initié par l’augmentation de la biodisponibilité de l’adénosine extracellulaire qui déclenche les effets protecteurs via ses récepteurs A3 et A2A. Ceci peut expliquer, en partie, les effets cardioprotecteurs du ticagrelor décrit chez l’homme. L’ensemble de nos données conforte le rôle protecteur de l’ATP et de l’adénosine vis-à-vis de l’hypoxie au niveau endothélial et suggèrent un rôle bénéfique de ces médiateurs dans diverses ischémies notamment cardiaque, rénale ou cérébraleDuring cardiac ischemia, the lesion is triggered in the endothelium and progresses to the surrounding cardiomyocytes. Purinergic signalling plays an important role during ischemia/reperfusion (I/R) events. Many studies have been carried out to study the mechanisms of protection of nucleotides and nucleosides, without studying their specific roles on the endothelium. In this work, we report an increase in extracellular concentrations of ATP and adenosine from the endothelium exposed to hypoxia. We report a protective effect of extracellular ATP and a complementary role of the P2 and P1 receptors. P2 receptors protective effects involve the PI3K, ERK1/2, mKATP channel signalling and also involve NOS. The protection mediated by the P1 receptors involves the MEK/ERK1/2, PKA and NOS. In a second step, we describe a new cytoprotective mechanism of ticagrelor, independent of the blood element and its antiplatelet anti-aggregating effect. This mechanism is initiated by the increased of extracellular adenosine bioavailability, which triggers protective effects via its A3 and A2A receptors. This may explain, in part, the reported cardioprotective effects of the ticagrelor in clinical studies. Together, our data support the protective role of ATP and adenosine against deleterious effects ofendothelium hypoxia and suggest a beneficial role for these mediators in different ischemia, including cardiac, renal or cerebral ischemia
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Pereira, Maria Margarida Ribeirinho. "The role of hypoxia driven adenosinergic pathway in the malignant features of bladder cancer cells." Master's thesis, 2020. http://hdl.handle.net/10316/93875.
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Dissertação de Mestrado em Bioquímica apresentada à Faculdade de Ciências e TecnologiaIntrodução: A hipóxia é uma característica comum dos tumores sólidos e desempenha um papel crítico nas neoplasias malignas, incluindo o cancro da bexiga (CB). O factor induzível por hipóxia-1α (HIF-1α) desempenha um papel importante na regulação da resposta das células tumorais sujeitas ao stress hipóxico que resulta em alterações metabólicas e na ativação de mecanismos de sobrevivência. As células hipóxicas sobreexpressam as ecto-nucleotidases CD39 e CD73 que estão envolvidas na geração de adenosina extracelular. Este nucleosídeo atua como um importante regulador de processos inflamatórios em condições fisiológicas mas no cancro, inibe o sistema imunitário permitindo que as células cancerígenas escapem ao controlo do sistema imunitário. Além disso, existem evidências que associam a ativação da via adenosinérgica em resposta à hipóxia com a agressividade tumoral. No entanto, os mecanismos que estão subjacentes a este processo não estão completamente clarificados.Objetivo: Explorar o papel patofisiológico da via adenosinérgica mediada por hipóxia nas características malignas do CB e avaliar a contribuição do HIF-1α e da adenosina nesses processos biológicos.Métodos: Duas linhas celulares humanas de CB, UM-UC3 e HT-1376, foram expostas a hipóxia usando um sistema anaeróbio GasPakTM EZ na ausência e na presença do inibidor do HIF-1α (Digoxina). A expressão do HIF-1α, CD39, CD73, dos receptores de adenosina A2A e A2B e do PD-L1 foi avaliada por Western blot. Os níveis extracelulares de adenosina no sobrenadante foram medidos usando um kit comercial de medição de adenosina. A proliferação celular e a quimiossensibilidade à cisplatina foram avaliadas pelo ensaio de WST-1. A migração celular foi determinada pelo ensaio de scratch. Os marcadores de superfície e os fatores de transcrição da transição epitelial-mesenquimal foram analisados por qPCR. Estas experiências foram realizadas em condições de normóxia na presença de adenosina.Resultados: Ambas as linhas celulares em condições de hipóxia estabilizaram o HIF-1α e ativaram a via adenosinérgica como demonstrado pela sobreexpressão das ecto-nucleotidases CD39 e CD73, produção de adenosina extracelular e sobreexpressão do receptor A2B. A hipóxia diminuiu a susceptibilidade das células de CB à cisplatina e aumentou a expressão do PD-L1, antecipando o desenvolvimento de mecanismos de evasão do sistema imunológico. A hipóxia induziu a transição epitelial-mesenquimal em ambas as linhas celulares e aumentou a capacidade de migração das células HT-1376, mas não das UM-UC3. O tratamento com adenosina exacerbou as características malignas das células de CB, semelhante às induzidas pelas condições de hipóxia. A Digoxina atenuou a expressão de HIF-1α nas células de CB em condições de hipóxia sem contudo prevenir a produção de adenosina extracelular e os seus efeitos pro-tumorais.Conclusão: A hipóxia ativou a via adenosinérgica nas células de CB e promoveu a agressividade tumoral ao interferir com a proliferação celular, quimiorresistência e capacidade de invasão. A adenosina desempenha um papel importante no efeito pro-tumoral da hipóxia. Assim sendo, estratégias terapêuticas incorporando inibidores da via hipóxia-CD39-CD73-A2BR podem ser benéficos no controlo da progressão tumoral e na resposta à terapia.
Introduction: Hypoxia is a common feature of solid tumors and a critical hallmark of malignant disease, including bladder cancer (BC). The hypoxia-inducible factor-1α (HIF-1α) is a crucial regulator of cancer cells response to hypoxia stress and results in metabolic changes and activation of survival mechanisms. Hypoxic cells upregulate the ecto-nucleotidases CD39 and CD73 that are involved in the generation of extracellular adenosine. This nucleoside in physiological conditions acts as an important regulator of inflammatory processes but in cancer, dampen the immune system allowing cancer cells to escape the immune control. Moreover, accumulating evidences suggest a link between the adenosinergic response to hypoxia and tumor aggressiveness. However, the mechanisms behind this process are not completely clarified.Objectives: To explore the pathophysiological role of the hypoxia-driven adenosinergic pathway on the malignant features of BC and to unravel the contribution of HIF-1α and of adenosine in those biological processes.Methods: Two human BC cell lines, UM-UC3 and HT-1376, were exposed to hypoxia using the GasPak ez anaerobe system in the absence and in the presence of a HIF-1α inhibitor (Digoxin). The expression of HIF-1α, CD39, CD73, adenosine receptors A2A and A2B and of PD-L1 were measured by Western blot. Extracellular levels of adenosine in supernatants were measured using an adenosine assay kit. Cell proliferation and chemosensitivity to cisplatin were evaluated using the WST-1 assay. Cell migration was assessed via a wound-healing assay. Epithelial-to-mesenchymal transition surface markers and transcription factors were detected by qPCR. A parallel set of experiments were conducted under normoxic conditions in the presence of adenosine.Results: Both cell lines under hypoxic conditions stabilized HIF-1α and activated the adenosinergic pathway as shown by the upregulation of CD39, CD73 and extracellular generation of adenosine, accompanied by an upregulation of the A2B receptor. Hypoxia impaired the susceptibility of BC cells to cisplatin and upregulates the expression of PD-L1, anticipating the development of an immune escape mechanism. Hypoxic stress induced epithelial-to-mesenchymal transition in both cell lines and increased the migratory rate of HT-1376 cells, but not of UM-UC3 cells. Treatment with adenosine exacerbated the malignant features of BC cells in a fashion similar to those induced by hypoxic conditions. Digoxin attenuated the protein expression of HIF-1α in BC cells under hypoxic conditions without preventing the extracellular production of adenosine and its pro-tumoral effects.Conclusion: Hypoxia activated the adenosinergic pathway in BC cells and promoted tumor aggressiveness by interfering with cell proliferation, chemoresistance and invasiveness. Adenosine has a high contribution to the tumor-promoting effects of hypoxia. Therefore, therapeutic strategies incorporating inhibitors of the hypoxia-CD39-CD73-A2BR pathway might be beneficial in controlling tumor growth and response to therapy.
Outro - This work was funded by National Funds via FCT (Foundation for Science and Technology) through the Strategic Project UIDB/04539/2020 and UIDP/04539/2020 (CIBB)
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Silva, Tiago Soares. "Interaction between ecto-5’-nucleotidase and adenosine A2A receptors in nerve terminals of mice prefrontal cortex." Master's thesis, 2013. http://hdl.handle.net/10316/24725.
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Dissertação de mestrado em Bioquímica, apresentada ao Departamento Ciências da Vida da Faculdade de Ciências e Tecnologia da Universidade de Coimbra.A ativação dos recetores de adenosina A2A (A2AR) é feita através da adenosina que pode ser produzida através do catabolismo do ATP libertado no meio extracelular. A ecto-5’-nucleotidase (e-5’N) desempenha um papel importante na formação de adenosina proveniente do catabolismo do ATP, e subsequentemente na ativação dos A2AR controlando assim a plasticidade sináptica. Após uma lesão cerebral, o ATP é libertado como um sinal aversivo provocando o aumento em simultâneo da atividade da e-5’N e da densidade dos A2AR. Isto levanta a hipótese de que a e-5’N e os A2AR podem encontrar-se co-localizados e poderá haver uma interação funcional entre eles. Este estudo tem como objetivos definir: i) a localização sináptica e sub-sináptica (regiões pré-, pós- e extra-sinápticas) da e-5’N focando principalmente no córtex pré-frontal (PFC) de ratinhos C57Bl/6 adultos, ii) a co-localização da e-5’N com os A2AR em fatias do PFC e em terminais nervosos corticais, iii) se a deleção genética dos A2AR afeta a densidade sináptica da e-5’N em regiões corticais, iv) a função da e-5’N na plasticidade sináptica do PFC, e por fim, v) se o envelhecimento afeta a densidade sináptica da e-5’N em regiões do PFC. A comparação por análise de Western blot da densidade da e-5’N em membranas totais e sinaptossomas do córtex pré-frontal revelou que a e-5’N se encontrava nos terminais nervosos (52.1 2.3%, n=4), mas não se encontrava tão enriquecida como nas membranas totais (72.5 3.1%, n=4). O fracionamento dos sinaptossomas do córtex pré-frontal mostrou a presença de duas isoformas diferentes da e-5’N, estando uma mais presente nas frações pré-sináptica e extra-sináptica (~50 kDa) e outra presente (~70 kDa) na fração pós-sináptica. Através de imunohistoquímica foi possível verificar uma aparente co-localização entre a e-5’N e os A2AR, estando mais presentes em neurónios e microglia, mas não com astrócitos. O “pull-down” dos A2AR em terminais nervosos do córtex pré-frontal revelou uma associação física entre os A2AR e a e-5’-N. A delecção genética dos A2AR não afetou significativamente os níveis de e-5’-N, no entanto verificou-se um ligeiro aumento nos níveis desta enzima. Estudos de eletrofisiologia em fatias de córtex pré-frontal incubadas com um antagonista seletivo dos A2AR (SCH 58261) demonstraram que a ativação dos A2AR era necessária para obter potenciação de longa duração (LTP); porém quando a e-5’N era inibida (com AOPCP), prevenindo a formação de adenosina, a transmissão sináptica basal sofria um efeito inibitório mas não se observaram diferenças significativas no fenómeno da LTP, desencadeado por 5 “trains” de estímulos de 300 Hz. Também foram avaliados através de HPLC os níveis basais de AMP e adenosina em sinaptossomas de córtex pré-frontal, e como esperado observou-se níveis aumentados de AMP na presença de AOPCP, uma vez que este nucleósido não estava a ser convertido em adenosina, no entanto os níveis de adenosina não se encontravam alterados significativamente; o que sugere que a contribuição da e-5’N para a formação de adenosina nos terminais nervosos do PFC não é significativa. Finalmente, analisou-se se a densidade sináptica da e-5’N era afetada pelo envelhecimento, para tal comparámos por imunoblot a densidade desta enzima em ratinhos jovens adultos (8-12 semanas de idade) e em ratinhos adultos (36-40 semanas de idade); porém, não se observaram diferenças significativas entre estes dois grupos de animais. Embora este trabalho tenha algumas questões que precisam de ser detalhadas com mais rigor, os resultados contribuem com novos dados sobre a relação entre a e-5’N e os A2AR no PFC, e poderão ser úteis para resolver questões relacionadas com disfunções do lobo frontal do cérebro.
The activation of adenosine A2A receptors (A2AR) is mediated by adenosine that can be originated from the extracellular catabolism of released ATP. Ecto-5’-nucleotidase (e-5’N) plays a key role in the formation of ATP-derived adenosine and in the subsequent activation of A2AR to control synaptic plasticity. Upon brain injury, ATP is released as a stress signal and both e-5’N and A2AR are up-regulated in parallel. This prompts the hypothesis that e-5’N and A2AR could be co-localized and co-regulated. The present study aims to define: i) the synaptic and sub-synaptic (pre-, post- and extra-synaptic regions) localization of e-5’N focusing in the prefrontal cortex (PFC) of adult C57Bl/6 mice, ii) the co-localization of e-5’N with A2AR in slices from the PFC and in cortical nerve terminals, iii) if the genetic deletion of A2AR affects the density of synaptic e-5’N in cortical regions, iv) the function of e-5’N in synaptic plasticity in the PFC, and finally v) if aging affects the density of synaptic e-5’N in PFC regions. The comparison by Western blot analysis of the density of e-5’N in prefrontal cortex total membranes and synaptosomes revealed that e-5’N, was present in nerve terminals (52.1 2.3%, n=4), but was not as enriched as in the bulk of total membranes (72.5 3.1%, n=4). The fractionation of prefrontal cortex synaptosomes unveiled the presence of two different isoforms of e-5’N, one being more present at the pre-synaptic and extra-synaptic fractions (~50 kDa) and the other (~70 kDa) at the post-synaptic fraction. By immunohistochemistry it was possible to observe an apparent co-localization of e-5’N with A2AR, mainly associated with neurons and microglia but not with astrocytes. The pull-down of A2AR revealed a physical association of A2AR with e-5’-N in nerve terminals from the prefrontal cortex. The genetic deletion of A2AR did not affect significantly the levels of e-5’-N, although it was found a slight increase in the levels of this enzyme. Electrophysiological studies in prefrontal cortex slices incubated with a selective antagonist of A2AR (SCH 58261) demonstrated that the activation of A2AR was necessary to obtain long term potentiation (LTP); however when e-5’N was blocked (with AOPCP), and consequently the adenosine formation was prevented, the basal synaptic transmission suffered an inhibitory effect but there were no significant changes in the LTP phenomenon, triggered by 5 trains of 300 Hz stimuli. We also evaluated by HPLC measurements the basal levels of AMP and adenosine in synaptosomes from the PFC and as expected it was observed that in the presence of AOPCP, the levels of AMP were increased, since this nucleoside was not converted into adenosine, nevertheless the levels of adenosine did not change significantly; suggesting that the contribution of e-5’N to adenosine formation in nerve terminals of PFC was not substantial. Finally we analysed whether the synaptic density of e-5’N was affected by the aging, thus we compared by immunoblot the density of this enzyme in young adult (8-12 weeks old) and in adult mice (36-40 weeks old); nevertheless, no significant differences were observed between these two groups of animals Although this work have some question that need to be more deeply investigated, the results give new insights about the relation between e-5’N and A2AR in the PFC, and could be useful to tackle questions regarding frontal lobe brain dysfunctions.
Books on the topic "Adenine nucleotides Receptors"
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Pharmacology of purine and pyrimidine receptors. San Diego, CA: Elsevier, 2011.
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1931-, Imai Shōichi, Nakazawa Mikio, and International Symposium on Adenosine and Adenine Nucleotides (4th : 1990 : Yamanaka Lake, Japan), eds. Role of adenosine and adenine nucleotides in the biological system: Metabolism, release, transport, receptors, transduction mechanisms and biological actions : proceedings of the 4th international symposium on adenosine and adenine nucleotides, Lake Yamanaka, Japan, 13-17 May, 1990. Amsterdam: Elsevier, 1991.
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1953-, Jacobson Kenneth Alan, and Jarvis Michael F, eds. Purinergic approaches in experimental therapeutics. New York: Wiley-Liss, 1997.
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Imai, Shoichi. Role of Adenosine and Adenine Nucleotides in the Biological System: Metabolism, Release, Transport, Receptors, Transduction Mechanisms and Biologica. Elsevier Science Ltd, 1991.
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W, Stone T., ed. Adenosine in the nervous system. London: Academic Press, 1991.
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1953-, Jacobson Kenneth Alan, Daly John W, and Manganiello V, eds. Purines in cellular signaling: Targets for new drugs. New York: Springer-Verlag, 1990.
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Daly, John W., and Kenneth A. Jacobson. Purines in Cellular Signaling: Targets for New Drugs. Springer, 1990.
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Jacobson, Kenneth A. Purines in Cellular Signaling: Targets for New Drugs. Springer, 2011.
Find full textBook chapters on the topic "Adenine nucleotides Receptors"
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Illes, P., K. Nieber, and W. Nörenberg. "Neuronal ATP Receptors." In Adenosine and Adenine Nucleotides: From Molecular Biology to Integrative Physiology, 77–84. Boston, MA: Springer US, 1995. http://dx.doi.org/10.1007/978-1-4615-2011-5_10.
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Kollias-Baker, Cynthia, John C. Shryock, and Luiz Belardinelli. "Myocardial Adenosine Receptors." In Adenosine and Adenine Nucleotides: From Molecular Biology to Integrative Physiology, 221–28. Boston, MA: Springer US, 1995. http://dx.doi.org/10.1007/978-1-4615-2011-5_26.
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Jacobson, Marlene A. "Molecular Biology of Adenosine Receptors." In Adenosine and Adenine Nucleotides: From Molecular Biology to Integrative Physiology, 5–13. Boston, MA: Springer US, 1995. http://dx.doi.org/10.1007/978-1-4615-2011-5_1.
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Hoppe, Edmund, and Martin J. Lohse. "Desensitization of A1 Adenosine Receptors." In Adenosine and Adenine Nucleotides: From Molecular Biology to Integrative Physiology, 133–38. Boston, MA: Springer US, 1995. http://dx.doi.org/10.1007/978-1-4615-2011-5_16.
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Burnstock, Geoffrey, and Noel J. Buckley. "The Classification of Receptors for Adenosine and Adenine Nucleotides." In Methods Used in Adenosine Research, 193–212. Boston, MA: Springer US, 1985. http://dx.doi.org/10.1007/978-1-4684-4886-3_11.
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Mustafa, S. Jamal, Ravi Marala, Worku Abebe, Neil Jeansonne, Hammed Olanrewaju, and Tahir Hussain. "Coronary Adenosine Receptors: Subtypes, Localization, and Function." In Adenosine and Adenine Nucleotides: From Molecular Biology to Integrative Physiology, 229–39. Boston, MA: Springer US, 1995. http://dx.doi.org/10.1007/978-1-4615-2011-5_27.
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Burnstock, Geoffrey. "Receptors for ATP at Peripheral Neuroeffector Junctions." In Adenosine and Adenine Nucleotides: From Molecular Biology to Integrative Physiology, 289–95. Boston, MA: Springer US, 1995. http://dx.doi.org/10.1007/978-1-4615-2011-5_33.
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Vanderhaeghen, Jean-Jacques, and Serge N. Schiffmann. "In Situ Hybridization of Adenosine Receptors in Brain." In Adenosine and Adenine Nucleotides: From Molecular Biology to Integrative Physiology, 21–26. Boston, MA: Springer US, 1995. http://dx.doi.org/10.1007/978-1-4615-2011-5_3.
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IJzerman, Ad P., Nora M. van der Wenden, Philip J. M. van Galen, and Ken A. Jacobson. "Molecular Modeling of Adenosine A1 and A2a Receptors." In Adenosine and Adenine Nucleotides: From Molecular Biology to Integrative Physiology, 27–37. Boston, MA: Springer US, 1995. http://dx.doi.org/10.1007/978-1-4615-2011-5_4.
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Song, Yejia, John Shryock, and Luiz Belardinelli. "Modulation of Cardiomyocyte Membrane Currents by A1 Adenosine Receptors." In Adenosine and Adenine Nucleotides: From Molecular Biology to Integrative Physiology, 97–102. Boston, MA: Springer US, 1995. http://dx.doi.org/10.1007/978-1-4615-2011-5_12.
Full textConference papers on the topic "Adenine nucleotides Receptors"
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Gordon, J. L. "ADENINE NUCLEOTIDES AND THEREGULATION OF VASCULAR TONE." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643719.
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ATP, although known mainly as an intracellular energy source, is also capable of acting extracellularly as a vasoactive agent of great potency, at concentrations around lμM or less. ADP is approximately equipotent with ATP in its actions on extracellular receptors in the vasculature.ATP and ADP can arise extracellularly through release from the cytoplasm of cellsexposed to damaging stimuli or by degranulation of platelets. The concentration of the nucleotides in the cytoplasm of most cells (including vascular endothelial and smooth muscle cells) is more than ImM, and the concentration in the dense storage granules of platelets approaches 1M. Thus, there is potential for very high localised concentrations of ATP and ADP in the plasma following platelet degranulation or damageto cells of the vessel well. Release from vascular endothelial and smooth muscle cells can occur with no loss of cell viability or leakage of cytoplasmic proteins.The vasoactivity of ATP and ADP is mediated via P2 purinoceptors. Vasodilation can be induced through the release of EDRF from endothelial cells or through stimulation of PGI2 production (PGI2 is a vasodilator in many, althoughnot all, arterial beds). Purinoceptor-mediated prostacyclin production can be stimulated from perfused vascular beds (e.g. theheart andthe lung), from isolated blood vessels or from cultured endothelial cells.In some blood vessels, purinoceptor-mediated vasoconstriction can be induced by direct actionon the vascular smooth muscle cells. The receptors responsible are sub-classified as P2X (which induce vasoconstriction) and P2Y (whichinduce vasodilation). The P2Y purinoceptor that mediates EDRF production is very similar to that which is responsible for PGI2 production, although there are some intriguing differences inthe potency of ATP analogs at stimulating these two responses, even on the same cells. The intracellular mechanisms responsible have not yet been fully elucidated, but it appears that elevation of intracellular calcium is likely to play a causal role.Adenosine, which is the product of ATP and ADP metabolism by nucleotidases, can also induce vasodilation in many blood vessels, acting via P1] purinoceptors on the smooth muscle cells, but its potency is often less than that of ATP and ADP.The fate of adenine nucleotides released into the plasma is determined by ectonucleotidases on the luminal surface of the endothelial cells, not by enzymes in the blood itself (the half-life of ATP in samples of blood or plasma is many minutes, while in the microcirculation the half-life isless than one second). Endothelial ectonucleotidases have been detected in several vascular beds, and many of their characteristics are now known. These enzymes are distinct entities from the P2 purinoceptors on endothelium, as shown by the marked differences in potency of several ATP analogs as P2 receptor stimulants and as substrates for the nucleotidases.In summary, vascular endothelial and smooth muscle cells respond to extracellularATP and ADP, and can also metabolise thesenucleotides extracellularly by ectonucleotidases. In addition, ATP and ADP can be selectively released from the cells of the vessel wall and from activated platelets. Thus, the endothelial pericellular environment can be the site of complex interactions by which vascular tone is regulated through the release, actions and metabolism ofextracellular nucleotides.
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Vanhoutte, Paul M. "PLATELETS, ENDOTHELIUM AND VASOSPASM." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643722.
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The endothelium can secrete both relaxing and contracting substances. One of the most powerful stimuli to the release of the former are thrombin and aggregating platelets. This contributes to the protective role of the endothelium against inappropriate intraluminal platelet aggregation and coagulation in blood vessels with an intact intima. Thrombin-induced, endothelium-dependent relaxations have been obtained in isolated arteries of different species, including humans. Endothelium-dependent relaxations can be evoked by autologous platelets in isolated blood vessels of the dog, pig and rat; they can be obtained in canine coronary arteries with human platelets. The major platelet-products involved in these endothelium-dependent relaxations are 5-hydroxytryptamine (serotonin) and the adenine nucleotides. Although platelet-activating factor (PAF) can evoke endothelium-dependent relaxation it only does so at concentrations much higher than those occurring under physiological conditions; since the relaxations are not prevented by PAF-antagonists, they are non-specific in nature.The receptor mediating the endothelium-dependent relaxations to serotonin released from the aggregating platelets can be subtyped as a S1~(5HT1) serotonergic receptor;those mediating the response to the adenine nucleotides as P2y-purinergic receptors. In the absence of the endothelium aggregating platelets cause contractions of vascular smooth muscle; these are mediated by a mixture of S1-like and S2~serotoner-gic receptors in coronary arteriesof the dog, and by S2-serotonergic receptors in those of the pig. Thus, in the porcine coronary artery, the S2-serotonergic antagonist ketanserin markedly enhances the platelet-induced endothelium-dependent relaxation. After previous (four weeks) injury, the regenerated endothelium of the porcine coronary artery loses the ability to respond to serotonin,and is unable to prevent the constrictionsevoked by aggregating platelets. The endothelium-dependent relaxations of porcine coronary arteries evoked by aggregating platelets are potentiated by chronic treatmentof the donor animals with cod liver oil. These studies emphasize the protective roleof the endothelial cells against the vasoconstriction (vasospasm) induced by aggregating platelets. This role is depressed after previous injury, and can be facilitatedby dietary adj ustments.
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Gray, S. J., and S. Heptinstall. "INTERACTIONS BETWEEn PGE2 AND INHIBITORS OF PLATELET AGGREGATION THAT ACT THROUGH cAMP." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643582.
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PGE2 has a biphasic effect on platelet aggregation with low concentrations of the prostaglandin potentiating aggregation and high concentrations inhibiting it. In this investigation we have studied the interaction of PGE2 with agents that inhibit platelet aggregation through an effect on cAMP. The agents chosen raise the level of cAMP in platelets by different mechanisms: PGI2, PGD9 and adenosine combine with specific surface-located receptors and stimulate adenylate cyclase (AC) via a guanine nucleotide-binding protein (GNBP), forskolin stimulates AC directly, and AH-P 719 and DN 9693 inhibit cAMP phosphodiesterase (PDE). ADP-induced platelet aggregation was measured in platelet-rich plasma and cAMP was measured in platelets labelled with 3H-adenine.PGE2 alone potentiated platelet aggregation at concentrations from 10™8 -10™6 M and inhibited aggregation at 10™5M. PGE2 did not reduce cAMP levels at any concentration and increased cAMP levels at concentrations > 10™6 M, profcably by stimulating AC.PGI2 (10™9 -10™8 M), PGD2 (10™7 -5×10™6 M) and adenosine (8×l0™5-2×10™4 M) increased the level of cAMP in platelets and inhibited aggregation these changes were reversed by low concentrations of PGE2 (10™8-10™6M).Forskolin (5×10™6-2.5×10™5M), AH-P 719 (10™7-10™5M) and DN 9693 (5×10™6 -10™5M) increased the level of cAMP in platelets and inhibited aggregation. However, PGE2 did not reverse the inhibitory effects of these particular agents. In contrast, PGE2 potentiated the effects of the agents at all the concentrations of PGE2 that were tested (10™8-10™5M).The different results obtained with PGE2 in combination with agents that act via surface-located receptors compared with agents that stimulate AC directly or act through PDE, suggest that PGE2 may potentiate platelet aggregation by acting at a point between the platelet receptor and AC i.e. GNBP.PGE2 is one of the major prostaglandins synthesised by human microvascular endothelial cells and interstitial cells of the renal medulla. Since it reverses the inhibitory effects of some AC stimulators but adds to those of PDE inhibitors, the latter may have greater potential as anti-thrombotic agents in the micro-circulation and intra-renal circulation.
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Jefferson, J. R., J. T. Harmon, and G. A. Jamieson. "ADP-BINDING SITES IN PLATELETS: CHARACTERIZATION BY PHOTOAFFINITY LABELING AND BINDING STUDIES WITH FIXED PLATELETS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644463.
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Attempts to photoaffinity label platelet ADP receptors with 2-azidoADP have not been successful possibly due to the absence of a spacer arm between the nucleotide and the photolabile group. We have synthesized a probe having a long spacer arm by coupling 2-(3-aminopropylthio)-ADP to succinimidyl 4-3H-azidobenzoate. Labeling competable by ADP could not demonstrated with intact platelets. With isolated platelet membranes, three bands (Mr 140,000, 110,000 and 46,000) were labeled that were not competed by ADP while three other bands (Mr 188,000, 92,000 and 51,000) were competable by 100 uM ADP.Another problem in characterizing ADP receptors has been complications due to ADP metabolism and secretion from the dense granules. To avoid this problem we have measured the binding of ADP and analogues to formalin-fixed platelets. ADP bound to two sites (Kl, 0.35 ± 0.04 uM; R1, 160,000 ± 20,000 sites/platelet; K2 7.9 ± 2.0 uM; R2, 400,000 ± 40,000 sites/platelet) with low non-specific binding: these values are in agreement with ADP concentrations required for activation. Affinity at the high affinity site was in the sequence ADP(0.35 uM)=ATP(0.4 uM)›2-MeS.ADP(6.8 uM)› GDP(49 uM) › AMP(360 uM); adenosine did not compete. Binding at the high affinity site was blocked by pMBS (EC50 250 uM) and 5-fluoro-sulfonylbenzoyladenosine (EC50 1 mM). This is the first report of photoaffinity labeling of putative ADP receptors. Our experiments with fixed platelets suggest that they may be useful in testing agonists, antagonists and inhibitors in the absence of complications due to secretion and metabolism.