Localization of Nucleoside Triphosphate Diphosphohydrolase-1 (NTPDase1) and NTPDase2 in Pancreas and Salivary Gland

Kittel, Ágnes; Pelletier, Julie; Bigonnesse, François; Guckelberger, Olaf; Kordás, Krisztina; Braun, Norbert; Robson, Simon C.; Sévigny, Jean

doi:10.1369/jhc.3a6167.2004

Cited by 35 publications

(31 citation statements)

References 49 publications

(61 reference statements)

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“…1A). NTPDase1 was also detected in acinar cells, and NTPDase2 was detected in the connective tissue areas surrounding the islets and acini, as described previously (29). NTPDase3 expression was observed exclusively in Langerhans islet cells.…”

Section: Murine Langerhans Islet Cells Express Ntpdase3supporting

confidence: 80%

Identification of the ectonucleotidases expressed in mouse, rat, and human Langerhans islets: potential role of NTPDase3 in insulin secretion

Lavoie

Fausther

Kauffenstein

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Extracellular nucleotides and adenosine regulate endocrine pancreatic functions such as insulin secretion by Langerhans islet ␤-cells via the activation of specific P2 and P1 receptors. Membrane-bound ectonucleotidases regulate the local concentration of these ligands and consequently control the activation of their receptors. The objective of this study was to identify and localize the major ectonucleotidases, namely NTPDases and ecto-5=-nucleotidase, present in the endocrine pancreas. In addition, the potential implication of ecto-ATPase activity on insulin secretion was investigated in the rat ␤-cell line INS-1 (832/13). The localization of ectonucleotidase activity and protein was carried out in situ by enzyme histochemistry and immunolocalization in mouse, rat, and human pancreas sections. NTPDase1 was localized in all blood vessels and acini, and NTPDase2 was localized in capillaries of Langerhans islets and in peripheral conjunctive tissue, whereas NTPDase3 was detected in all Langerhans islet cell types. Interestingly, among the mammalian species tested, ecto-5=-nucleotidase was present only in rat Langerhans islet cells, where it was coexpressed with NTPDase3. Notably, the inhibition of NTPDase3 activity by BG0136 and NF279 facilitated insulin release from INS-1 (832/13) cells under conditions of low glycemia, probably by affecting P2 receptor activation. NTPDase3 activity also regulated the inhibitory effect of exogenous ATP in the presence of a high glucose concentration most likely by controlling adenosine production. In conclusion, all pancreatic endocrine cells express NTPDase3 that was shown to modulate insulin secretion in rat INS-1 (832/13) ␤-cells. Ecto-5=-nucleotidase is expressed in rat Langerhans islet cells but absent in human and mouse endocrine cells.nucleoside triphosphate diphosphohydrolase; ecto-5=-nucleotidase/ CD73; P2 receptors; purinergic signaling; INS-1 (832/13) INSULIN IS SYNTHESIZED AND SECRETED in a highly regulated manner by ␤-cells, the dominant cell population in Langerhans islets. Physiological glycemia elevations raise the rate of metabolism in ␤-cells, thereby leading to an increase in intracellular ATP/ADP ratio and the closure of ATP-sensitive K ϩ channels (43). The ensuing cell membrane depolarization triggers the opening of the voltage-dependent Ca 2ϩ channels and the increase of intracellular Ca 2ϩ concentration, leading to the exocytosis of insulin-containing granules (43). Upon glucose stimulation, insulin secretion from ␤-cells is accompanied by the release of ATP (11,25,28,49) at maximal concentrations reaching up to 25 M at the cell surface (20). Extracellular ATP and ADP and synthetic P2 receptor agonists such as 2-methylthioadenosine 5=-triphosphate and adenosine 5=-(␤-thio)diphosphate increase glucose-induced insulin secretion in a variety of species, including rat and human (9,17,26,39). The situation is not as clear in the mouse, since extracellular nucleotides were reported to either diminish (34,44,46) or increase insulin secretion (2, 45), suggesting th...

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Section: Murine Langerhans Islet Cells Express Ntpdase3supporting

confidence: 80%

Identification of the ectonucleotidases expressed in mouse, rat, and human Langerhans islets: potential role of NTPDase3 in insulin secretion

Lavoie

Fausther

Kauffenstein

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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“…In human pancreas, immuno-and histochemistry indicate that active NTPDase 1 (CD39) is not detected in acini or ducts (26). In recent studies on pancreatic tissue from mice, ATPase and ADPase activities determined by inorganic phosphate assays were significantly lower in CD39Ϫ/Ϫ mice when compared with control mice (17). Immuno-and histochemistry revealed that acini and ducts express both CD39 and CD39L1, i.e.…”

Section: Discussionmentioning

confidence: 98%

ATP-consuming and ATP-generating Enzymes Secreted by Pancreas

Yegutkin

Samburski

Jalkanen

et al. 2006

Journal of Biological Chemistry

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Pancreatic acini release ATP in response to various stimuli, including cholecystokinin octapeptide (CCK-8), as we show in the present study. There were indications that pancreatic juice also contains enzymes that could hydrolyze ATP during its passage through the ductal system. The aim of this study was to determine which ATP-degrading and possibly ATP-generating enzymes were present in pancreatic secretion. For this purpose, pancreatic juice was collected from anesthetized rats stimulated with infusion of CCK-8. Purine-converting activities in juice samples were assayed by TLC using either [ 3 H]AMP to adenosine. Along with highly active hydrolytic enzymes, there were also ATP-generating enzymes in pancreatic juice, adenylate kinase, and NDP kinase, capable of sequentially phosphorylating AMP via ADP to ATP. Activities of nonspecific phosphatases, nucleotide pyrophosphatase/ phosphodiesterases, and adenosine deaminase were negligible. Taken together, CCK-8 stimulation of pancreas causes release of both ATP-consuming and ATP-generating enzymes into pancreatic juice. This newly discovered richness of secreted enzymes underscores the importance of purine signaling between acini and pancreatic ducts lumen and implies regulation of the purine-converting enzymes release.Extracellular ATP and other purines mediate signaling between cells by means of neural transmission, paracrine, and autocrine effects. There are several important steps in this purinergic cascade including release of ATP, interaction with specific P2 purinergic receptors on the target cells, and not the least, ATP-degrading and -converting enzymes, which determine the balance between nucleotides and nucleosides and thus activation of P2 versus P1 (adenosine) receptors.Extracellular nucleotides can be hydrolyzed by a number of enzymes, such as ecto-nucleoside triphosphate diphosphohydrolases from the NTPDase 2 (CD39) family that hydrolyze nucleoside 5Ј-tri-and diphosphates (1). Ecto-nucleotide pyrophosphatase/phosphodiesterases (NPP) have broad substrate specificity and can convert ATP to AMP and PP i (2). Ecto-5Ј-nucleotidases (CD73) further hydrolyze AMP to adenosine, which can be taken up into the cell by specific Na ϩ -dependent nucleoside transporters or converted into inosine by adenosine deaminase. Ecto-alkaline phosphatases have broad action and dephosphorylate 5Ј-tri-, di-, and monophosphates. In addition to these degradation and inactivation pathways, there are also counteracting ATP-generating pathways, which include reverse nucleotide transphosphorylation by adenylate kinase and nucleoside diphosphate kinase (NDPK). These kinases, which play roles in intracellular signaling and in DNA and RNA synthesis among others, are also expressed on surfaces of different cell types and can contribute to nucleotide balance (3).In cardiovascular system and in respiratory epithelia, a number of enzymes handling nucleotides are well characterized. In human blood, soluble NPP, 5Ј-nucleotidase, and adenosine deaminase, as well as adenylate and NDP kinases, c...

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“…Furthermore, the TMDs of human NTPDase1 are important for folding and sorting as well as for optimal enzymatic activity and activation by cholesterol [127]. While NTPDase1 has been found to be localized in the apical as well as basolateral surface [95,[128][129][130], when expressed in the polarized Madin-Darby canine kidney (MDCK) cells, it is targeted to the apical side of the membrane. The N-terminal TMD contains an apical targeting signal; however, neither the N-nor the C-terminal domain was required for apical targeting, suggesting that an additional targeting signal is located at the ectodomain.…”

Section: Membrane Topologymentioning

confidence: 99%

Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

Purinergic Signalling

879

922

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Ecto-nucleotidases play a pivotal role in purinergic signal transmission. They hydrolyze extracellular nucleotides and thus can control their availability at purinergic P2 receptors. They generate extracellular nucleosides for cellular reuptake and salvage via nucleoside transporters of the plasma membrane. The extracellular adenosine formed acts as an agonist of purinergic P1 receptors. They also can produce and hydrolyze extracellular inorganic pyrophosphate that is of major relevance in the control of bone mineralization. This review discusses and compares four major groups of ectonucleotidases: the ecto-nucleoside triphosphate diphosphohydrolases, ecto-5′-nucleotidase, ecto-nucleotide pyrophosphatase/phosphodiesterases, and alkaline phosphatases. Only recently and based on crystal structures, detailed information regarding the spatial structures and catalytic mechanisms has become available for members of these four ecto-nucleotidase families. This permits detailed predictions of their catalytic mechanisms and a comparison between the individual enzyme groups. The review focuses on the principal biochemical, cell biological, catalytic, and structural properties of the enzymes and provides brief reference to tissue distribution, and physiological and pathophysiological functions.

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Localization of Nucleoside Triphosphate Diphosphohydrolase-1 (NTPDase1) and NTPDase2 in Pancreas and Salivary Gland

Cited by 35 publications

References 49 publications

Identification of the ectonucleotidases expressed in mouse, rat, and human Langerhans islets: potential role of NTPDase3 in insulin secretion

Identification of the ectonucleotidases expressed in mouse, rat, and human Langerhans islets: potential role of NTPDase3 in insulin secretion

ATP-consuming and ATP-generating Enzymes Secreted by Pancreas

Cellular function and molecular structure of ecto-nucleotidases

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