Ectonucleotidases: Some recent developments and a note on nomenclature

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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.

Section: General Properties and Functional Rolementioning

confidence: 99%

Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

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“…Nucleosides and nucleotides mediate a variety of biological functions in both short-and long-term signaling functions (development, regeneration, differentiation, proliferation, and cell death) [1,12]. These events are mediated by the activation of P1 (for adenosine) or P2 (for ATP, ADP, UDP, and UTP) receptors and are controlled by the action of ectonucleotidases [15]. The ecto-nucleoside triphosphate diphosphohydrolases refer to a family of cell-surface enzymes that hydrolyze extracellular ATP and ADP to AMP.…”

Section: Introductionmentioning

confidence: 99%

NTPDase3 and ecto-5′-nucleotidase/CD73 are differentially expressed during mouse bladder cancer progression

Rockenbach

Braganhol

Dietrich

et al. 2014

According to the World Health Organization, bladder cancer is the seventh most common cancer among men in the world. The current treatments for this malignancy are not efficient to prevent the recurrence and progression of tumors. Then, researches continue looking for better therapeutic targets which can end up in new and more efficient treatments. One of the recent findings was the identification that the purinergic system was involved in bladder tumorigenesis. The ectonucleotidases, mainly ecto-5′-nucleotidase/CD73 have been revealed as new players in cancer progression and malignity. In this work, we investigated the NTPDase3 and ecto-5′-nucleotidase/CD73 expression in cancer progression in vivo. Bladder tumor was induced in mice by the addition of 0.05 % of N-butyl-N-(hydroxybutyl)-nitrosamine (BBN) in the drinking water for 4, 8, 12, 18, and 24 weeks. After this period, mice bladders were removed for histopathology analysis and immunofluorescence assays. The bladder of animals which has received BBN had alterations, mainly inflammation, in initial times of tumor induction. After 18 weeks, mice's bladder has developed histological alterations similar to human transitional cell carcinoma. The cancerous urothelium, from mice that received BBN for 18 and 24 weeks, presented a weak immunostaining to NTPDase3, in contrast to an increased expression of ecto-5′-nucleotidase/CD73. The altered expression of NTPDase3 and ecto-5′-nucleotidase/ CD73 presented herein adds further evidence to support the idea that alterations in ectonucleotidases are involved in bladder tumorigenesis and reinforce the ecto-5′-nucleotidase/ CD73 as a future biomarker and/or a target for pharmacological therapy of bladder cancer.

“…Purinergic signaling in the cochlea involving the P2Y and P2X receptors is regulated by ecto-enzymes, including the ecto-nucleotidases (ecto-nucleoside triphosphate diphosphohydrolases; NTPDase), and ecto-5′-nucleotidase, which dephosphorylate extracellular nucleotides such as ATP and UTP through a cascade of di-and monophosphate nucleosides [13]. In the case of hydrolysis of ATP to adenosine, this enables activation of adenosine (P1) receptors.…”

Section: Introductionmentioning

confidence: 99%

“…Eight mammalian P2Y receptors have been identified, and in the case of P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 11 , they directly mediate Ca 2+ signaling via the G qa -phospholipase C b (PLC)-inositol trisphosphate (IP 3 )-gated Ca 2+ store pathway. P2Y 12 , P2Y 13 , and P2Y 14 receptor signal transduction utilizes G ia -mediated inhibition of adenylate cyclase and hence reduction in cAMP (reviewed by [14,15]). Endogenous P2Y receptor signaling may also engage additional pathways, including stimulation of adenylate cyclase (P2Y 11 ), and activation of phospholipase D, phospholipase A2, MEK/MAP kinase, and Rhodependent kinase (for ERK signaling) [15].…”

Section: Introductionmentioning

confidence: 99%

“…The P2Y-PLC pathway may also mediate Ca 2+ entry through transient receptor potential (TRP) channels, gated by membranebound diacylglycerol (DAG) [16,17]. In broad terms, P2Y 1 and P2Y 11 are ATP preferring [14]; P2Y 12 and P2Y 13 are ADP preferring [14]; rat P2Y 2 and P2Y 4 orthologs are equally activated by ATP and UTP [18] and P2Y 6 is preferentially activated by UDP, with ADP > ATP [19]; P2Y 14 is activated most potently by UDP-glucose [14]. However, the functional significance of the agonist preferences of the P2Y receptors needs to be matched to the endogenous ligand environment.…”

Section: Introductionmentioning

confidence: 99%

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Differential expression of P2Y receptors in the rat cochlea during development

Huang

Thorne

Vlajkovic

et al. 2010

Purinergic signaling has broad physiological significance to the hearing organ, involving signal transduction via ionotropic P2X receptors and metabotropic G-protein-coupled P2Y and P1 (adenosine), alongside conversion of nucleotides and nucleosides by ectonucleotidases and ecto-nucleoside diphosphokinase. In addition, ATP release is modulated by acoustic overstimulation or stress and involves feedback regulation. Many of these principal elements of the purinergic signaling complex have been well characterized in the cochlea, while the characterization of P2Y receptor expression is emerging. The present study used immunohistochemistry to evaluate the expression of five P2Y receptors, P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 12 , during development of the rat cochlea. Commencing in the late embryonic period, the P2Y receptors studied were found in the cells lining the cochlear partition, associated with establishment of the electrochemical environment which provides the driving force for sound transduction. In addition, early postnatal P2Y 2 and P2Y 4 protein expression in the greater epithelial ridge, part of the developing hearing organ, supports the view that initiation and regulation of spontaneous activity in the hair cells prior to hearing onset is mediated by purinergic signaling. Sub-cellular compartmentalization of P2Y receptor expression in sensory hair cells, and diversity of receptor expression in the spiral ganglion neurons and their satellite cells, indicates roles for P2Y receptormediated Ca 2+ -signaling in sound transduction and auditory neuron excitability. Overall, the dynamics of P2Y receptor expression during development of the cochlea complement the other elements of the purinergic signaling complex and reinforce the significance of extracellular nucleotide and nucleoside signaling to hearing.