Adenosine(5') oligophospho-(5') guanosines and guanosine(5') oligophospho-(5') guanosines in human platelets.

Schlüter, Hartmut; Grobeta, I; Bachmann, Jürgen; Kaufmann, R; Giet, M. van der; Tepel, Martín; Nofer, Jerzy–Roch; Assmann, Gerd; Karas, Michael; Jankowski, Joachim; Zidek, Walter

doi:10.1172/jci119882

Cited by 48 publications

(48 citation statements)

References 28 publications

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“…Ap4A and other Np,,N may participate in the regulation of purine nucleotides [5,6], in cellular response to stress [2], in the control of cell proliferation [7], in the interferon action [8], as transition state analogues of some kinases [9], etc. Ap1A and other dinucleoside polyphosphates are present in chromaffin granules of bovine adrenal medulla [10][11][12], in synaptic terminals [13] and in human blood platelets [14]. After an appropriate stimulus they are released from these storage sites to the blood and through their interaction with some still not well defined purine receptors [15][16][17][18][19] they may modulate a variety of processes such as vascular tone [20], platelet aggregation [20,21], neurotransmission [22], cell proliferation [3,7,23], etc.…”

Section: Introductionmentioning

confidence: 99%

T4 DNA ligase synthesizes dinucleoside polyphosphates

et al. 1998

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T4 DNA iigase (EC 6.5.1.1), one of the most widely used enzymes in genetic engineering, transfers AMP from the E-AMP complex to tripolyphosphate, ADP, ATP, GTP or dATP producing p4A, Ap3A, Ap4A, Ap4G and Ap4dA, respectively. Nicked DNA competes very effectively with GTP for the synthesis of ApIG and, conversely, tripolyphosphate (or GTP) inhibits the iigation of DNA by the ligase. As T4 DNA ligase has similar requirements for ATP as the mammalian DNA ligase(s), the latter enzyme(s) could also synthesize dinucleoside polyphosphates. The present report may be related to the recent finding that human Fhit (fragile histidine triad) protein, encoded by the FHIT putative tumor suppressor gene, is a typical dinucleoside 5',5"-Pa,pa-triphosphate (Ap3A) hydrolase (EC 3.6.1.29).

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Section: Introductionmentioning

confidence: 99%

T4 DNA ligase synthesizes dinucleoside polyphosphates

et al. 1998

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“…Diadenosine polyphosphates are stored in secretory vesicles containing ATP and are released after synaptic terminal stimulation (Pintor et al, 1992. Other members of the dinucleotide family are the diguanosine polyphosphates (Gp n G), a group of naturally occurring substances first isolated from platelets and more recently from neurosecretory vesicles (Schlü ter et al, 1998;Jankowski et al, 2003). Once in the extracellular medium, dinucleotides are able to activate presynaptic purinergic receptors.…”

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confidence: 99%

GABA Modulates Presynaptic Signalling Mediated by Dinucleotides on Rat Synaptic Terminals

Gómez‐Villafuertes

Pintor²,

Gualix³

et al. 2004

J Pharmacol Exp Ther

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Diadenosine pentaphosphate (Ap 5 A) elicits Ca 2ϩ transients in isolated rat midbrain synaptic terminals acting through specific ionotropic dinucleotide receptors. The activation of GABA B receptors by baclofen changes the sigmoidal concentrationresponse curve for Ap 5 A (EC 50 ϭ 44 M) into biphasic curves. Thus, when GABA B receptors are activated, the curve shows a high-affinity component in the picomolar range (EC 50 ϭ 77 pM) and a low-affinity component in the micromolar range (EC 50 ϭ 17 M). In addition, in the presence of GABA or baclofen, Ap 5 A calcium responses are increased up to 50% over the control values. Saclofen, a specific antagonist of GABA B receptors, blocks the potentiatory effect of baclofen. As occurs with Ap 5 A, GABA B receptors are also capable to modulate diguanosine pentaphosphate (Gp 5 G)-induced calcium responses. The combination of immunocytochemical and microfluorimetric techniques carried out on single synaptic terminals have shown that in the presence of baclofen, 64% of the terminals responding to 100 M Ap 5 A are also able to respond to 100 nM Ap 5 A. This value is close to the percentage of synaptic terminals responding to Ap 5 A and labeled with the anti-GABA B receptor antibody (69%). The activity of cyclic AMP-dependent protein kinase (PKA) seems to be involved in the potentiatory effect of GABA B receptors on Ap 5 A calcium responses, because PKA activation by forskolin or dibutiryl cyclic AMP blocks the potentiatory effect of baclofen, whereas PKA inhibition facilitates calcium signaling mediated by Ap 5 A. These results demonstrate that the activation of presynaptic GABA B receptors is able to modulate dinucleotide responses in synaptic terminals. P 1 ,P n -Di(adenosine-5Ј) polyphosphates (Ap n A) constitute a group of compounds structurally related to ATP. Members of this family are formed by two adenosine moieties linked by their 5Ј ends through phosphate chains of variable length. Diadenosine polyphosphates are stored in secretory vesicles containing ATP and are released after synaptic terminal stimulation (Pintor et al., 1992. Other members of the dinucleotide family are the diguanosine polyphosphates (Gp n G), a group of naturally occurring substances first isolated from platelets and more recently from neurosecretory vesicles (Schlü ter et al., 1998;Jankowski et al., 2003). Once in the extracellular medium, dinucleotides are able to activate presynaptic purinergic receptors. Extracellular actions of Ap n A in the central nervous system include the modulation of the firing rate and the inhibition/facilitation of the synaptic transmission in neurons (Klishin et al., 1994;Fröhlich et al., 1996). It has been demonstrated that rat midbrain synaptic terminals respond to the addition of ATP and Ap n A with an increase in the intrasynaptosomal calcium concentration . The effect of ATP was mediated through P2X receptors with P2X 3 -like pharmacology . However, Ap n A effect seemed to be mediated through different receptors, termed dinucleotide receptors, which are a...

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“…Recently, di(adenosine-5Ј) heptaphosphate (Ap 7 A) has been isolated in human platelets and has been postulated to play a role in the control of vascular tone (6). Furthermore, dinucleoside polyphosphates containing adenosine and guanosine (adenosine-5Ј oligophospho 5Ј-guanosines (Ap n G; n ϭ 3-6)) or containing two guanosines (guanosine-5Ј oligophospho 5Ј-guanosines (Gp n G; n ϭ 3-6)) were identified in human platelets (7). Ap n G (n ϭ 5-6) have a vasoconstrictive effect, whereas Gp n G do not affect vascular tone in the isolated perfused rat kidney.…”

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confidence: 99%

“…Both Ap n Gs and Gp n Gs (with n ϭ 3-6) are growthstimulating factors of VSMCs. (7). Several purine receptor subtypes (P2 receptors) mediating the actions of dinucleoside polyphosphates have been established with different physiological effects (8,9).…”

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Dinucleotides as Growth-promoting Extracellular Mediators

Jankowski

Hagemann

Tepel

et al. 2001

Journal of Biological Chemistry

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To further evaluate the pathogenesis of hypertension, there is a continued interest in the identification of novel endogenous compounds with growth-stimulating effects on vascular smooth muscle cells (VSMCs).1 In this context, novel endogenous nucleotides have been recognized as powerful vasoactive messengers.In the last decade dinucleoside polyphosphates received considerable attention in view of their multiple biological and pharmacological activities. Dinucleoside polyphosphates were identified in prokaryotic (1), eukaryotic, and mammalian cells (2). Di(adenosine-5Ј) tri-and tetraphosphates (Ap 3 A, Ap 4 A) were the first dinucleoside polyphosphates to be identified in human platelets (3, 4). Di(adenosine-5Ј) pentaphosphate (Ap 5 A) and di(adenosine-5Ј) hexaphosphate (Ap 6 A) have been described as vasoconstrictive substances isolated from human platelets (5). Recently, di(adenosine-5Ј) heptaphosphate (Ap 7 A) has been isolated in human platelets and has been postulated to play a role in the control of vascular tone (6). Furthermore, dinucleoside polyphosphates containing adenosine and guanosine (adenosine-5Ј oligophospho 5Ј-guanosines (Ap n G; n ϭ 3-6)) or containing two guanosines (guanosine-5Ј oligophospho 5Ј-guanosines (Gp n G; n ϭ 3-6)) were identified in human platelets (7). Ap n G (n ϭ 5-6) have a vasoconstrictive effect, whereas Gp n G do not affect vascular tone in the isolated perfused rat kidney. Both Ap n Gs and Gp n Gs (with n ϭ 3-6) are growthstimulating factors of VSMCs. (7). Several purine receptor subtypes (P2 receptors) mediating the actions of dinucleoside polyphosphates have been established with different physiological effects (8, 9). The P2 receptors are divided into two families of ligand-gated ion channel and G protein-coupled receptors termed P2X and P2Y receptor, respectively. There are eight mammalian P2X receptors (P2X 1-8 ) (10, 11) and five mammalian P2Y receptors (P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 11 ) that have been cloned (9).From these results the question arose as to whether P 1 ,P 2 -dinucleoside diphosphates containing two adenosine or guanosine groups or an adenosine and a guanosine group also occur in humans. There is one report on the existence of diadenosine diphosphate (Ap 2 A) isolated from human cardiac tissue (12). In contrast to Ap 2 A the P 1 ,P 2 -dinucleoside diphosphates Ap 2 G and Gp 2 G have not been described as endogenous substances so far in the literature.Here the existence of diadenosine diphosphate (Ap 2 A), adenosine guanosine diphosphate (Ap 2 G), as well as diguanosine diphosphate (Gp 2 G) in releasable granules of human platelets is shown for the first time and their growth-stimulating effect on cultured vascular smooth muscle cells is described. MATERIALS AND METHODS ChemicalsHPLC water (gradient grade) and acetonitrile were from Merck (Germany). All other substances were purchased from Sigma (Germany). * This study was supported by a grant of the Deutsche Forschungsgemeinschaft (DFG: Schl 406/2-1). The costs of publication of this article w...

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Adenosine(5') oligophospho-(5') guanosines and guanosine(5') oligophospho-(5') guanosines in human platelets.

Cited by 48 publications

References 28 publications

T4 DNA ligase synthesizes dinucleoside polyphosphates

T4 DNA ligase synthesizes dinucleoside polyphosphates

GABA Modulates Presynaptic Signalling Mediated by Dinucleotides on Rat Synaptic Terminals

Dinucleotides as Growth-promoting Extracellular Mediators

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