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Role of Ectonucleotidases in Health and Disease
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Role of Ectonucleotidases in Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (20 May 2023) | Viewed by 6093

Special Issue Editor

Dr. Gilles Kauffenstein

E-Mail Website
Guest Editor
UMR INSERM 1260, Centre de Recherche en Biomédecine de Strasbourg, Université de Strasbourg, 67084 Strasbourg, France
Interests: vascular biology; aortic stenosis; platelet physiology; purinergic signalling; ectonucleotidases; ectopic calcification

Special Issue Information

Dear Colleagues, 

Purinergic signaling, which defines intercellular communication through nucleotides (P2) and nucleosides (P1) receptors, controls a diversity of biological processes. The bioavailability and relative proportions of extracellular nucleotides/nucleosides is tightly regulated by a set of membrane-bound ectonucleotidases. The role of these enzymes is multiple and complex. Through hydrolyzing nucleotides, ectonucleotidases control P2 receptor activation and prevent their desensitization; additionally, by hydrolyzing adenine nucleotides, they drive adenosine accumulation a molecule with remarkable anti-inflammatory properties. Ectonucleotidases also contribute to regulate phosphate and pyrophosphate homeostasis, impacting bone physiology but also soft tissue mineralization.

This Special Issue of the International Journal of Molecular Science is dedicated to the latest discoveries on ectonucleotidases in health and disease, from their physiological role to their therapeutic potential.

Dr. Gilles Kauffenstein
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (5 papers)

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Research

22 pages, 7670 KiB  
Article
Differential Influences of Endogenous and Exogenous Sensory Neuropeptides on the ATP Metabolism by Soluble Ectonucleotidases in the Murine Bladder Lamina Propria
by Alejandro Gutierrez Cruz, Mafalda S. L. Aresta Branco, Mahsa Borhani Peikani and Violeta N. Mutafova-Yambolieva
Int. J. Mol. Sci. 2023, 24(21), 15650; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242115650 - 27 Oct 2023
Viewed by 650
Abstract
Bladder urothelium and suburothelium/lamina propria (LP) have prominent sensory and transducer functions with the active participation of afferent neurons and urothelium-derived purine mediators such as adenosine 5’-triphosphate (ATP), adenosine 5’-diphosphate (ADP), and adenosine (ADO). Effective concentrations of purines at receptor targets depend significantly [...] Read more.
Bladder urothelium and suburothelium/lamina propria (LP) have prominent sensory and transducer functions with the active participation of afferent neurons and urothelium-derived purine mediators such as adenosine 5’-triphosphate (ATP), adenosine 5’-diphosphate (ADP), and adenosine (ADO). Effective concentrations of purines at receptor targets depend significantly on the extracellular degradation of ATP by ectonucleotidases (ENTDs). We recently reported the regulated release of soluble ENTDs (s-ENTDs) in the LP and the consequent degradation of ATP to ADP, AMP, and ADO. Afferent neurons in the LP can be activated by urothelial ATP and release peptides and other transmitters that can alter the activity of cells in their vicinity. Using a murine decentralized ex vivo detrusor-free bladder model, 1,N6-etheno-ATP (eATP) as substrate, and sensitive HPLC-FLD methodologies, we found that exogenous neuropeptides calcitonin gene-related peptide (CGRP), substance P (Sub P), neurokinin A (NKA), and pituitary adenylate cyclase-activating polypeptide [PACAP (1-38)] all increased the degradation of eATP by s-ENTDs that were released in the LP spontaneously and/or during bladder filling. Using antagonists of neuropeptide receptors, we observed that endogenous NKA did not modify the ATP hydrolysis by s-ENTDs, whereas endogenous Sub P increased both the constitutive and distention-induced release of s-ENTDs. In contrast, endogenous CGRP and PACAP (1-38) increased the distention-induced, but not the spontaneous, release of s-ENTDs. The present study puts forward the novel idea that interactions between peptidergic and purinergic signaling mechanisms in the LP have an impact on bladder excitability and functions by regulating the effective concentrations of adenine purines at effector cells in the LP. Full article
(This article belongs to the Special Issue Role of Ectonucleotidases in Health and Disease)
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18 pages, 1452 KiB  
Article
NTPDase1/CD39 Ectonucleotidase Is Necessary for Normal Arterial Diameter Adaptation to Flow
by Julie Favre, Charlotte Roy, Anne-Laure Guihot, Annick Drouin, Manon Laprise, Marc-Antoine Gillis, Simon C. Robson, Eric Thorin, Jean Sévigny, Daniel Henrion and Gilles Kauffenstein
Int. J. Mol. Sci. 2023, 24(20), 15038; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242015038 - 10 Oct 2023
Viewed by 942
Abstract
NTPDase1/CD39, the major vascular ectonucleotidase, exerts thrombo-immunoregulatory function by controlling endothelial P2 receptor activation. Despite the well-described release of ATP from endothelial cells, few data are available regarding the potential role of CD39 as a regulator of arterial diameter. We thus investigated the [...] Read more.
NTPDase1/CD39, the major vascular ectonucleotidase, exerts thrombo-immunoregulatory function by controlling endothelial P2 receptor activation. Despite the well-described release of ATP from endothelial cells, few data are available regarding the potential role of CD39 as a regulator of arterial diameter. We thus investigated the contribution of CD39 in short-term diameter adaptation and long-term arterial remodeling in response to flow using Entpd1−/− male mice. Compared to wild-type littermates, endothelial-dependent relaxation was modified in Entpd1−/− mice. Specifically, the vasorelaxation in response to ATP was potentiated in both conductance (aorta) and small resistance (mesenteric and coronary) arteries. By contrast, the relaxing responses to acetylcholine were supra-normalized in thoracic aortas while decreased in resistance arteries from Entpd1−/− mice. Acute flow-mediated dilation, measured via pressure myography, was dramatically diminished and outward remodeling induced by in vivo chronic increased shear stress was altered in the mesenteric resistance arteries isolated from Entpd1−/− mice compared to wild-types. Finally, changes in vascular reactivity in Entpd1−/− mice were also evidenced by a decrease in the coronary output measured in isolated perfused hearts compared to the wild-type mice. Our results highlight a key regulatory role for purinergic signaling and CD39 in endothelium-dependent short- and long-term arterial diameter adaptation to increased flow. Full article
(This article belongs to the Special Issue Role of Ectonucleotidases in Health and Disease)
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22 pages, 10703 KiB  
Article
Sensory Neurons, PIEZO Channels and PAC1 Receptors Regulate the Mechanosensitive Release of Soluble Ectonucleotidases in the Murine Urinary Bladder Lamina Propria
by Mafalda S. L. Aresta Branco, Alejandro Gutierrez Cruz, Mahsa Borhani Peikani and Violeta N. Mutafova-Yambolieva
Int. J. Mol. Sci. 2023, 24(8), 7322; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24087322 - 15 Apr 2023
Cited by 3 | Viewed by 1338
Abstract
The urinary bladder requires adequate concentrations of extracellular adenosine 5′-triphosphate (ATP) and other purines at receptor sites to function properly. Sequential dephosphorylation of ATP to ADP, AMP and adenosine (ADO) by membrane-bound and soluble ectonucleotidases (s-ENTDs) is essential for achieving suitable extracellular levels [...] Read more.
The urinary bladder requires adequate concentrations of extracellular adenosine 5′-triphosphate (ATP) and other purines at receptor sites to function properly. Sequential dephosphorylation of ATP to ADP, AMP and adenosine (ADO) by membrane-bound and soluble ectonucleotidases (s-ENTDs) is essential for achieving suitable extracellular levels of purine mediators. S-ENTDs, in particular, are released in the bladder suburothelium/lamina propria (LP) in a mechanosensitive manner. Using 1,N6-etheno-ATP (eATP) as substrate and sensitive HPLC-FLD methodology, we evaluated the degradation of eATP to eADP, eAMP and eADO in solutions that were in contact with the LP of ex vivo mouse detrusor-free bladders during filling prior to substrate addition. The inhibition of neural activity with tetrodotoxin and ω-conotoxin GVIA, of PIEZO channels with GsMTx4 and D-GsMTx4 and of the pituitary adenylate cyclase-activating polypeptide type I receptor (PAC1) with PACAP6-38 all increased the distention-induced but not spontaneous release of s-ENTDs in LP. It is conceivable, therefore, that the activation of these mechanisms in response to distention restricts the further release of s-ENTDs and prevents excessive hydrolysis of ATP. Together, these data suggest that afferent neurons, PIEZO channels, PAC1 receptors and s-ENTDs form a system that operates a highly regulated homeostatic mechanism to maintain proper extracellular purine concentrations in the LP and ensure normal bladder excitability during bladder filling. Full article
(This article belongs to the Special Issue Role of Ectonucleotidases in Health and Disease)
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18 pages, 4845 KiB  
Article
Overexpression of TcNTPDase-1 Gene Increases Infectivity in Mice Infected with Trypanosoma cruzi
by Natália Lins da Silva-Gomes, Leonardo Alexandre de Souza Ruivo, Claudia Moreira, Marcelo Meuser-Batista, Cristiane França da Silva, Denise da Gama Jaen Batista, Stênio Fragoso, Gabriel Melo de Oliveira, Maria de Nazaré Correia Soeiro and Otacilio C. Moreira
Int. J. Mol. Sci. 2022, 23(23), 14661; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314661 - 24 Nov 2022
Viewed by 1074
Abstract
Ecto-nucleoside triphosphate diphosphohydrolases (NTPDases) are enzymes located on the surface of the T. cruzi plasma membrane, which hydrolyze a wide range of tri-/-diphosphate nucleosides. In this work, we used previously developed genetically modified strains of Trypanosoma cruzi (T. cruzi), hemi-knockout (KO +/−) and [...] Read more.
Ecto-nucleoside triphosphate diphosphohydrolases (NTPDases) are enzymes located on the surface of the T. cruzi plasma membrane, which hydrolyze a wide range of tri-/-diphosphate nucleosides. In this work, we used previously developed genetically modified strains of Trypanosoma cruzi (T. cruzi), hemi-knockout (KO +/−) and overexpressing (OE) the TcNTPDase-1 gene to evaluate the parasite infectivity profile in a mouse model of acute infection (n = 6 mice per group). Our results showed significantly higher parasitemia and mortality, and lower weight in animals infected with parasites OE TcNTPDase-1, as compared to the infection with the wild type (WT) parasites. On the other hand, animals infected with (KO +/−) parasites showed no mortality during the 30-day trial and mouse weight was more similar to the non-infected (NI) animals. In addition, they had low parasitemia (45.7 times lower) when compared with parasites overexpressing TcNTPDase-1 from the hemi-knockout (OE KO +/−) group. The hearts of animals infected with the OE KO +/− and OE parasites showed significantly larger regions of cardiac inflammation than those infected with the WT parasites (p < 0.001). Only animals infected with KO +/− did not show individual electrocardiographic changes during the period of experimentation. Together, our results expand the knowledge on the role of NTPDases in T. cruzi infectivity, reenforcing the potential of this enzyme as a chemotherapy target to treat Chagas disease (CD). Full article
(This article belongs to the Special Issue Role of Ectonucleotidases in Health and Disease)
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16 pages, 3536 KiB  
Article
CD73-Mediated Formation of Extracellular Adenosine Is Responsible for Adenosine A2A Receptor-Mediated Control of Fear Memory and Amygdala Plasticity
by Ana Patrícia Simões, Francisco Q. Gonçalves, Daniel Rial, Samira G. Ferreira, João Pedro Lopes, Paula M. Canas and Rodrigo A. Cunha
Int. J. Mol. Sci. 2022, 23(21), 12826; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112826 - 24 Oct 2022
Cited by 9 | Viewed by 1509
Abstract
Adenosine A2A receptors (A2AR) control fear memory and the underlying processes of synaptic plasticity in the amygdala. In other brain regions, A2AR activation is ensured by ATP-derived extracellular adenosine formed by ecto-5′-nucleotidase or CD73. We now tested whether [...] Read more.
Adenosine A2A receptors (A2AR) control fear memory and the underlying processes of synaptic plasticity in the amygdala. In other brain regions, A2AR activation is ensured by ATP-derived extracellular adenosine formed by ecto-5′-nucleotidase or CD73. We now tested whether CD73 is also responsible to provide for the activation of A2AR in controlling fear memory and amygdala long-term potentiation (LTP). The bilateral intracerebroventricular injection of the CD73 inhibitor αβ-methylene ADP (AOPCP, 1 nmol/ventricle/day) phenocopied the effect of the A2AR blockade by decreasing the expression of fear memory, an effect disappearing in CD73-knockout (KO) mice and in forebrain neuronal A2AR-KO mice. In the presence of PPADS (20 μM) to eliminate any modification of ATP/ADP-mediated P2 receptor effects, both AOPCP (100 μM) and the A2AR antagonist, SCH58261 (50 nM), decreased LTP magnitude in synapses of projection from the external capsula into the lateral amygdala, an effect eliminated in slices from both forebrain neuronal A2AR-KO mice and CD73-KO mice. These data indicate a key role of CD73 in the process of A2AR-mediated control of fear memory and underlying synaptic plasticity processes in the amygdala, paving the way to envisage CD73 as a new therapeutic target to interfere with abnormal fear-like emotional processing. Full article
(This article belongs to the Special Issue Role of Ectonucleotidases in Health and Disease)
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