Neuronal release of soluble nucleotidases and their role in neurotransmitter inactivation

Todorov, Latchezar D.; Mihaylova-Todorova, Svetlana T.; Westfall, Timothy D.; Sneddon, Peter; Kennedy, Charles; Bjur, Richard A.; Westfall, David P.

doi:10.1038/387076a0

Cited by 225 publications

(166 citation statements)

References 23 publications

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“…NTPDase1 was also found to be incorporated in microparticles of human and mouse plasma, where it may play a role in the exchange of regulatory signals between leucocytes and vascular cells [158] and in exosomes from diverse cancer cell types [159]. Release of soluble nucleotidases from stimulated sympathetic nerves innervating the guinea pig vas deferens nerve endings has previously been reported but the nature of the enzyme has not been determined [160,161].…”

Section: Soluble Formsmentioning

confidence: 99%

Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

Purinergic Signalling

854

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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Section: Soluble Formsmentioning

confidence: 99%

Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

Purinergic Signalling

854

922

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“…Cellular responses are induced by binding to two classes of P2 receptors: G proteincoupled P2Y receptors and ligand-gated P2X ion channels (1)(2)(3)(4)(5)(6). The ''purinergic signaling'' effects are converted and terminated via successive dephosphorylation of the nucleotides by a cascade of membrane-bound enzymes (7)(8)(9)(10)(11). Nucleoside triphosphate diphosphohydrolases (NTPDases, EC 3.6.1.5) and more specifically the cell surface-located NTPDase1-3 and -8 are the dominant ectonucleotidases relevant to P2 receptor-mediated signaling (10).…”

mentioning

confidence: 99%

Structural insight into signal conversion and inactivation by NTPDase2 in purinergic signaling

Zebisch

Sträter

2008

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

111

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Cell surface-located nucleoside triphosphate diphosphohydrolases (NTPDase1, -2, -3, and -8) are oligomeric integral membrane proteins responsible for signal conversion and inactivation in extracellular nucleotide-mediated ''purinergic'' signaling. They catalyze the sequential hydrolysis of the signaling molecule ATP via ADP to AMP. Here we present the structure of the extracellular domain of Rattus norvegicus NTPDase2 in an active state at resolutions between 1.7 Å and 2.1 Å in four different forms: (i) apo form, (ii) ternary complex with the nonhydrolyzable ATP analog AMPPNP and cofactor Ca 2؉ , (iii) quaternary complex with Ca 2؉ and bound products AMP and phosphate, and (iv) binary product complex with AMP only. Analysis of the ATP (analog) binding mode explains the importance of several residues for activity and allows suggestion of a catalytic mechanism. The carboxylate group of E165 serves as a catalytic base and activates a water molecule, which is well positioned for nucleophilic attack on the terminal phosphate. Based on analysis of the two product complex structures in which AMP adopts different conformations, a substrate binding mode for ADP hydrolysis is proposed. This allows for an understanding of how the same hydrolytic site can be engaged in ATP and ADP but not AMP hydrolysis.

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“…Although it is well established that the breakdown of ATP is mediated by membrane-bound ectonucleotidases, studies have indicated that soluble nucleotidases, probably released from sympathetic nerves, are also involved in ATP breakdown to adenosine [131,141]. Studies have shown that a single PTZ injection led to significantly increased ATP, ADP and AMP hydrolysis in rat blood serum (40-50%) for up to 24 h [15].…”

Section: Epilepsy Seizures and Ectonucleotidasesmentioning

confidence: 99%

“…ATP is stored in the synaptic vesicle together with other transmitters and, after nerve stimulation, this molecule is released into the synaptic cleft [131]. In addition, ATP is released from non-neuronal cells stimulated by a paracrine mechanism [60].…”

Section: Introductionmentioning

confidence: 99%

NTPDase and 5'‐nucleotidase activities in physiological and disease conditions: New perspectives for human health

et al. 2007

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Abstract. Extracellular nucleotides and nucleosides act as signaling molecules involved in a wide spectrum of biological effects. Their levels are controlled by a complex cell surface-located group of enzymes called ectonucleotidases. There are four major families of ectonucleotidases, nucleoside triphosphate diphosphohydrolases (NTPDases/CD39), ectonucleotide pyrophosphatase/phosphodiesterases (E-NPPs), alkaline phosphatases and ecto-5'-nucleotidase. In the last few years, substantial progress has been made toward the molecular identification of members of the ectonucleotidase families and their enzyme structures and functions. In this review, there is an emphasis on the involvement of NTPDase and 5'-nucleotidase activities in disease processes in several tissues and cell types. Brief background information is given about the general characteristics of these enzymes, followed by a discussion of their roles in thromboregulatory events in diabetes, hypertension, hypercholesterolemia and cancer, as well as in pathological conditions where platelets are less responsive, such as in chronic renal failure. In addition, immunomodulation and cell-cell interactions involving these enzymes are considered, as well as ATP and ADP hydrolysis under different clinical conditions related with alterations in the immune system, such as acute lymphoblastic leukemia (ALL), Bchronic lymphocytic leukemia (B-CLL) and infections associated with human immunodeficiency virus (HIV). Finally, changes in ATP, ADP and AMP hydrolysis induced by inborn errors of metabolism, seizures and epilepsy are discussed in order to highlight the importance of these enzymes in the control of neuronal activity in pathological conditions. Despite advances made toward understanding the molecular structure of ectonucleotidases, much more investigation will be necessary to entirely grasp their role in physiological and pathological conditions.

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Neuronal release of soluble nucleotidases and their role in neurotransmitter inactivation

Cited by 225 publications

References 23 publications

Cellular function and molecular structure of ecto-nucleotidases

Cellular function and molecular structure of ecto-nucleotidases

Structural insight into signal conversion and inactivation by NTPDase2 in purinergic signaling

NTPDase and 5'‐nucleotidase activities in physiological and disease conditions: New perspectives for human health

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