Specificity of the ecto‐ATPase inhibitor ARL 67156 on human and mouse ectonucleotidases

Lévesque, Sébastien A.; Lavoie, Élise G.; Lecka, Joanna; Bigonnesse, François; Sévigny, Jean

doi:10.1038/sj.bjp.0707361

Cited by 182 publications

(183 citation statements)

References 58 publications

(101 reference statements)

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“…It is noteworthy that NPPs prefer alkaline pHs for activity. In our hands, recombinant human NPP1 and NPP3 had only low ATPase activities (compared with those of NTPDases) [17], suggesting that the hydrolysis of dinucleoside polyphosphates may be a more important physiological function of NPPs.…”

Section: Introductionmentioning

confidence: 69%

“…The ATP analogue 6-N, Ndiethyl-D-β,γ-dibromomethylene ATP (ARL 67156) is another commercially available ecto-ATPase inhibitor that does not affect significantly purinoceptors. Recent reports demonstrated that ARL 67156 is a weak competitive inhibitor of NTPDase1, NTPDase3 and NPP1, with K i for the human enzymes of 11± 3, 18± 4 and 12± 3 µM, respectively [17,68]. Another ATP analogue, 8-thiobutyladenosine 5′-triphosphate (8-BuS-ATP), and 1-naphthol-3,6-disulfonic acid (BG0136), appear of interest, but so far they have only been characterised on a NTPDaseactive fraction from bovine spleen membranes [69,70].…”

Section: Inhibitors Of Ectonucleotidasesmentioning

confidence: 99%

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Ectonucleotidases in the kidney

Shirley

Vekaria

Sévigny

2009

Purinergic Signalling

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Members of all four families of ectonucleotidases, namely ectonucleoside triphosphate diphosphohydrolases (NTPDases), ectonucleotide pyrophosphatase/ phosphodiesterases (NPPs), ecto-5′-nucleotidase and alkaline phosphatases, have been identified in the renal vasculature and/or tubular structures. In rats and mice, NTPDase1, which hydrolyses ATP through to AMP, is prominent throughout most of the renal vasculature and is also present in the thin ascending limb of Henle and medullary collecting duct. NTPDase2 and NTPDase3, which both prefer ATP over ADP as a substrate, are found in most nephron segments beyond the proximal tubule. NPPs catalyse not only the hydrolysis of ATP and ADP, but also of diadenosine polyphosphates. NPP1 has been identified in proximal and distal tubules of the mouse, while NPP3 is expressed in the rat glomerulus and pars recta, but not in more distal segments. Ecto-5′-nucleotidase, which catalyses the conversion of AMP to adenosine, is found in apical membranes of rat proximal convoluted tubule and intercalated cells of the distal nephron, as well as in the peritubular space. Finally, an alkaline phosphatase, which can theoretically catalyse the entire hydrolysis chain from nucleoside triphosphate to nucleoside, has been identified in apical membranes of rat proximal tubules; however, this enzyme exhibits relatively high K m values for adenine nucleotides. Although information on renal ectonucleotidases is still incomplete, the enzymes' varied distribution in the vasculature and along the nephron suggests that they can profoundly influence purinoceptor activity through the hydrolysis, and generation, of agonists of the various purinoceptor subtypes. This review provides an update on renal ectonucleotidases and speculates on the functional significance of these enzymes in terms of glomerular and tubular physiology and pathophysiology.

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Section: Introductionmentioning

confidence: 69%

Section: Inhibitors Of Ectonucleotidasesmentioning

confidence: 99%

Ectonucleotidases in the kidney

Shirley

Vekaria

Sévigny

2009

Purinergic Signalling

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“…E-mail: lovatt@upenn.edu or nedergaard@ urmc.rochester.edu. only partially inhibits ATP dephosphorylation (17)(18)(19), suggesting that several NTPdases-including CD39, NTPDase-2 and -3, and alkaline phosphatase-are functional in brain tissue.…”

Section: Resultsmentioning

confidence: 99%

Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity

Lovatt

Xu²,

Liu³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

240

217

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Adenosine is a potent anticonvulsant acting on excitatory synapses through A1 receptors. Cellular release of ATP, and its subsequent extracellular enzymatic degradation to adenosine, could provide a powerful mechanism for astrocytes to control the activity of neural networks during high-intensity activity. Despite adenosine's importance, the cellular source of adenosine remains unclear. We report here that multiple enzymes degrade extracellular ATP in brain tissue, whereas only Nt5e degrades AMP to adenosine. However, endogenous A1 receptor activation during cortical seizures in vivo or heterosynaptic depression in situ is independent of Nt5e activity, and activation of astrocytic ATP release via Ca 2+ photolysis does not trigger synaptic depression. In contrast, selective activation of postsynaptic CA1 neurons leads to release of adenosine and synaptic depression. This study shows that adenosine-mediated synaptic depression is not a consequence of astrocytic ATP release, but is instead an autonomic feedback mechanism that suppresses excitatory transmission during prolonged activity.purinergic signaling | purine | glia | calcium signaling S everal lines of work over the past three decades have documented that adenosine acts as an endogenous anticonvulsant (1-3). The extracellular concentration of adenosine increases during seizures, and it has been proposed that status epilepticus is a result of loss of adenosine signaling (4). Conversely, mice lacking A1 receptors exhibit a decreased threshold for seizure propagation (5-7). Adenosine can be generated in the cytosol of neurons as a consequence of the metabolic exhaustion and released directly, as adenosine, via the equilibrative nucleoside transporters (ENTs)-e.g., the ubiquitously expressed ENT1 and ENT2 (8, 9). Alternatively, adenosine is released indirectly, as ATP followed by extracellular enzymatic catabolism to adenosine. The CNS expresses several ectoenzymes, including nucleoside triphosphate diphosphohydrolases (NTPDases; e.g., CD39, NTPDase-2), ectonucleotide pyrophosphatase/phosphodiesterases (e.g., autotaxin), and ecto-5′-nucleotidases (CD73/Nt5e, prostatic acid phosphatase, and alkaline phosphatase) (10-12). Although the regional and cellular activity patterns for each of these enzymes have not been fully explored, exogenous addition of ATP to ex vivo preparations has shown that all regions of the mammalian brain can dephosphorylate ATP to AMP through an ADP intermediate, whereas dephosphorylation of AMP to adenosine occurs primarily in the striatum and olfactory bulb (11). However, the presence of ectoenzymes does not prove that extracellular conversion of ATP to adenosine plays a physiological role, because extracellular adenosine is rapidly recirculated back into the cytosol by ENT1 and ENT2 (13). Further, ATP is released in small quantities during cell-cell signaling, and the effective diffusion of adenosine is limited because of the potent reuptake mechanisms (14). Thus, it is possible that extracellularly generated adenosine is transported back...

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“…In contrast to ␣,␤-methylene ADP, it did not significantly recover arteriolar constrictions to ATP: 1 Ϯ 1% constriction to ATP and 7.1 Ϯ 3% constriction to ATP following preincubation in ARL-67156 (P ϭ 0.09, Mann-Whitney test, n ϭ 8 each). In a recent study of the effect of ARL-67156 on recombinant mouse and human CD39 family members, Levesque et al (21) reported that mouse CD39 is only 50% inhibited by ARL-67156 when the ratio of antagonist to ATP is 10:1. This may account for the relatively small recovery of constrictions to ATP after ARL-67156 treatment.…”

Section: Resultsmentioning

confidence: 99%

Loss of purinergic vascular regulation in the colon during colitis is associated with upregulation of CD39

Neshat¹,

deVries²,

Barajas-Espinosa³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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Neshat S, deVries M, Barajas-Espinosa AR, Skeith L, Chisholm SP, Lomax AE. Loss of purinergic vascular regulation in the colon during colitis is associated with upregulation of CD39. Am J Physiol Gastrointest Liver Physiol 296: G399 -G405, 2009. First published December 12, 2008 doi:10.1152/ajpgi.90450.2008.-Evidence from patients with inflammatory bowel disease (IBD) and animal models suggests that inflammation alters blood flow to the mucosa, which precipitates mucosal barrier dysfunction. Impaired purinergic sympathetic regulation of submucosal arterioles, the resistance vessels of the splanchnic vasculature, is one of the defects identified during IBD and in mouse models of IBD. We hypothesized that this may be a consequence of upregulated catabolism of ATP during colitis. In vivo and in vitro video microscopy techniques were employed to measure the effects of purinergic agonists and inhibitors of CD39, an enzyme responsible for extracellular ATP catabolism, on the diameter of colonic submucosal arterioles from control mice and mice with dextran sodium sulfate [DSS, 5% (wt/vol)] colitis. Using a luciferase-based ATP assay, we examined the degradation of ATP and utilized real-time PCR, Western blotting, and immunohistochemistry to examine the expression and localization of CD39 during colitis. Arterioles from mice with DSS colitis did not constrict in response to ATP (10 M) but did constrict in the presence of its nonhydrolyzable analog ␣,␤-methylene ATP (1 M). ␣,␤-Methylene ADP (100 M), an inhibitor of CD39, restored ATP-induced vasoconstriction in arterioles from mice with DSS-induced colitis. CD39 protein and mRNA expression was markedly increased during colitis. Immunohistochemical analysis demonstrated that, in addition to vascular CD39, F4/80-immunoreactive macrophages accounted for a large proportion of submucosal CD39 staining during colitis. These data implicate upregulation of CD39 in impaired sympathetic regulation of gastrointestinal blood flow during colitis. purinergic neurotransmission; ectonucleotidase; inflammation; sympathetic; vasoconstriction STUDIES OF PATIENTS WITH INFLAMMATORY bowel disease (IBD) and animal models of IBD have revealed alterations in gastrointestinal (GI) blood flow (2,15,22,26) and angiogenesis (4 -6). These changes may contribute to disease pathogenesis, inasmuch as defects in mucosal perfusion render the mucosal barrier susceptible to breakdown. One potential mechanism of altered mucosal blood flow is defective neural regulation of GI blood vessels during inflammation.Submucosal arterioles are the resistance vessels of the splanchnic vasculature and thus regulate mucosal perfusion (13,23,31). We previously identified a defect in sympathetic vasoconstrictor regulation of colonic submucosal arterioles in the 2,4,6-trinitrobenzene sulfonic acid (TNBS) mouse model of IBD (22). Neurally evoked vasoconstrictions in control mice were sensitive to ␣ 1 -adrenoceptor and purinergic receptor antagonism, and superfusion of ATP and phenylephrine caused robust vasoconstrictions. I...

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Specificity of the ecto‐ATPase inhibitor ARL 67156 on human and mouse ectonucleotidases

Cited by 182 publications

References 58 publications

Ectonucleotidases in the kidney

Ectonucleotidases in the kidney

Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity

Loss of purinergic vascular regulation in the colon during colitis is associated with upregulation of CD39

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