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Dissecting the Purinergic Signaling Puzzle
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Dissecting the Purinergic Signaling Puzzle

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 (30 November 2020) | Viewed by 62226

Special Issue Editors

Prof. Raquel Pérez-Sen

E-Mail Website
Guest Editor
Departamento de Bioquímica y Biología Molecular, Facultad de Veterinaria, Instituto Universitario de Investigación en Neuroquímica (IUIN), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdiSSC), Universidad Complutense Madrid, 28040 Madrid, Spain
Interests: purinergic signaling; P2X receptors; P2Y receptors; neuroprotection; neural cells; protein phosphatases; DUSPs; signaling cascades
Prof. Esmerilda G. Delicado

E-Mail Website
Guest Editor
Departamento de Bioquímica y Biología Molecular, Facultad de Veterinaria, Instituto Universitario de Investigación en Neuroquímica (IUIN), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdiSSC), Universidad Complutense Madrid, 28040 Madrid, Spain
Interests: purinergic signaling; P2X receptors; P2Y receptors; neuroprotection; astrocytes; neural cells; protein phosphatases; DUSPs; signaling cascades

Special Issue Information

Dear Colleagues,

Purinergic signaling represents an expanding field involved in the regulation of a plethora of physio-pathological processes in different tissues and systems. One interesting feature that characterizes the purinergic network and makes it more complex and interesting than the rest of neurotransmitter systems is the numerous components integrating into a multistep cascade called “purinome”. In order to better understand the physiological relevance of nucleotide signaling, it should be considered as a whole, having an integrative view of all these elements and their relationships. The purinergic system includes nucleotide and adenosine receptors, and enzymatic and transporter activities interconverting nucleotides and nucleosides and connecting the intra- and extracellular spaces to regulate purinergic messenger availability. The aim of this Special Issue is to cover different key components of the purinergic system, regarding how they interact and work together in a coordinate fashion to shape and modulate the final biological response.

Prof. Raquel Pérez-Sen
Prof. Esmerilda G. Delicado
Guest Editors

Manuscript Submission Information

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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.

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Keywords

  • purinergic signaling
  • P2X receptor
  • P2Y receptor
  • adenosine receptor
  • adenosine/nucleoside transporter
  • vesicular nucleotide transporter (VNUT)
  • ectoenzymes
  • nucleotide/nucleoside metabolism
  • purinome
  • intracellular pathways

Published Papers (18 papers)

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Editorial

Jump to: Research, Review

5 pages, 225 KiB  
Editorial
Dissecting the Purinergic Signaling Puzzle
by Raquel Pérez-Sen and Esmerilda G. Delicado
Int. J. Mol. Sci. 2021, 22(16), 8925; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168925 - 19 Aug 2021
Cited by 1 | Viewed by 1285
Abstract
Purinergic signaling regulates a plethora of physiological processes and is an expanding research field [...] Full article
(This article belongs to the Special Issue Dissecting the Purinergic Signaling Puzzle)

Research

Jump to: Editorial, Review

15 pages, 2649 KiB  
Article
Loss of P2Y12 Has Behavioral Effects in the Adult Mouse
by Rebecca L. Lowery, Monique S. Mendes, Brandon T. Sanders, Allison J. Murphy, Brendan S. Whitelaw, Cassandra E. Lamantia and Ania K. Majewska
Int. J. Mol. Sci. 2021, 22(4), 1868; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041868 - 13 Feb 2021
Cited by 17 | Viewed by 2817
Abstract
While microglia have been established as critical mediators of synaptic plasticity, the molecular signals underlying this process are still being uncovered. Increasing evidence suggests that microglia utilize these signals in a temporally and regionally heterogeneous manner. Subsequently, it is necessary to understand the [...] Read more.
While microglia have been established as critical mediators of synaptic plasticity, the molecular signals underlying this process are still being uncovered. Increasing evidence suggests that microglia utilize these signals in a temporally and regionally heterogeneous manner. Subsequently, it is necessary to understand the conditions under which different molecular signals are employed by microglia to mediate the physiological process of synaptic remodeling in development and adulthood. While the microglial purinergic receptor P2Y12 is required for ocular dominance plasticity, an adolescent form of experience-dependent plasticity, it remains unknown whether P2Y12 functions in other forms of plasticity at different developmental time points or in different brain regions. Using a combination of ex vivo characterization and behavioral testing, we examined how the loss of P2Y12 affects developmental processes and behavioral performance in adulthood in mice. We found P2Y12 was not required for an early form of plasticity in the developing visual thalamus and did not affect microglial migration into barrels in the developing somatosensory cortex. In adult mice, however, the loss of P2Y12 resulted in alterations in recognition and social memory, as well as anxiety-like behaviors, suggesting that while P2Y12 is not a universal regulator of synaptic plasticity, the loss of P2Y12 is sufficient to cause functional defects. Full article
(This article belongs to the Special Issue Dissecting the Purinergic Signaling Puzzle)
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18 pages, 3469 KiB  
Article
Nucleotides-Induced Changes in the Mechanical Properties of Living Endothelial Cells and Astrocytes, Analyzed by Atomic Force Microscopy
by Juan Carlos Gil-Redondo, Jagoba Iturri, Felipe Ortega, Raquel Pérez-Sen, Andreas Weber, María Teresa Miras-Portugal, José Luis Toca-Herrera and Esmerilda G. Delicado
Int. J. Mol. Sci. 2021, 22(2), 624; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020624 - 10 Jan 2021
Cited by 5 | Viewed by 2478
Abstract
Endothelial cells and astrocytes preferentially express metabotropic P2Y nucleotide receptors, which are involved in the maintenance of vascular and neural function. Among these, P2Y1 and P2Y2 receptors appear as main actors, since their stimulation induces intracellular calcium mobilization and activates signaling [...] Read more.
Endothelial cells and astrocytes preferentially express metabotropic P2Y nucleotide receptors, which are involved in the maintenance of vascular and neural function. Among these, P2Y1 and P2Y2 receptors appear as main actors, since their stimulation induces intracellular calcium mobilization and activates signaling cascades linked to cytoskeletal reorganization. In the present work, we have analyzed, by means of atomic force microscopy (AFM) in force spectroscopy mode, the mechanical response of human umbilical vein endothelial cells (HUVEC) and astrocytes upon 2MeSADP and UTP stimulation. This approach allows for simultaneous measurement of variations in factors such as Young’s modulus, maximum adhesion force and rupture event formation, which reflect the potential changes in both the stiffness and adhesiveness of the plasma membrane. The largest effect was observed in both endothelial cells and astrocytes after P2Y2 receptor stimulation with UTP. Such exposure to UTP doubled the Young’s modulus and reduced both the adhesion force and the number of rupture events. In astrocytes, 2MeSADP stimulation also had a remarkable effect on AFM parameters. Additional studies performed with the selective P2Y1 and P2Y13 receptor antagonists revealed that the 2MeSADP-induced mechanical changes were mediated by the P2Y13 receptor, although they were negatively modulated by P2Y1 receptor stimulation. Hence, our results demonstrate that AFM can be a very useful tool to evaluate functional native nucleotide receptors in living cells. Full article
(This article belongs to the Special Issue Dissecting the Purinergic Signaling Puzzle)
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Graphical abstract

17 pages, 2641 KiB  
Article
From Inflammation to the Onset of Fibrosis through A2A Receptors in Kidneys from Deceased Donors
by Elena Guillén-Gómez, Irene Silva, Núria Serra, Francisco Caballero, Jesús Leal, Alberto Breda, Rody San Martín, Marçal Pastor-Anglada, José A. Ballarín, Lluís Guirado and Montserrat M. Díaz-Encarnación
Int. J. Mol. Sci. 2020, 21(22), 8826; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228826 - 21 Nov 2020
Cited by 4 | Viewed by 2812
Abstract
Pretransplant graft inflammation could be involved in the worse prognosis of deceased donor (DD) kidney transplants. A2A adenosine receptor (A2AR) can stimulate anti-inflammatory M2 macrophages, leading to fibrosis if injury and inflammation persist. Pre-implantation biopsies of kidney donors (47 DD and [...] Read more.
Pretransplant graft inflammation could be involved in the worse prognosis of deceased donor (DD) kidney transplants. A2A adenosine receptor (A2AR) can stimulate anti-inflammatory M2 macrophages, leading to fibrosis if injury and inflammation persist. Pre-implantation biopsies of kidney donors (47 DD and 21 living donors (LD)) were used to analyze expression levels and activated intracellular pathways related to inflammatory and pro-fibrotic processes. A2AR expression and PKA pathway were enhanced in DD kidneys. A2AR gene expression correlated with TGF-β1 and other profibrotic markers, as well as CD163, C/EBPβ, and Col1A1, which are highly expressed in DD kidneys. TNF-α mRNA levels correlated with profibrotic and anti-inflammatory factors such as TGF-β1 and A2AR. Experiments with THP-1 cells point to the involvement of the TNF-α/NF-κB pathway in the up-regulation of A2AR, which induces the M2 phenotype increasing CD163 and TGF-β1 expression. In DD kidneys, the TNF-α/NF-κB pathway could be involved in the increase of A2AR expression, which would activate the PKA–CREB axis, inducing the macrophage M2 phenotype, TGF-β1 production, and ultimately, fibrosis. Thus, in inflamed DD kidneys, an increase in A2AR expression is associated with the onset of fibrosis, which may contribute to graft dysfunction and prognostic differences between DD and LD transplants. Full article
(This article belongs to the Special Issue Dissecting the Purinergic Signaling Puzzle)
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20 pages, 4567 KiB  
Article
Adenosine Metabolism in the Cerebral Cortex from Several Mice Models during Aging
by Alejandro Sánchez-Melgar, José Luis Albasanz, Mercè Pallàs and Mairena Martín
Int. J. Mol. Sci. 2020, 21(19), 7300; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197300 - 02 Oct 2020
Cited by 13 | Viewed by 2794
Abstract
Adenosine is a neuromodulator that has been involved in aging and neurodegenerative diseases as Alzheimer’s disease (AD). In the present work, we analyzed the possible modulation of purine metabolites, 5’nucleotidase (5′NT) and adenosine deaminase (ADA) activities, and adenosine monophosphate (AMP)-activated protein kinase (AMPK) [...] Read more.
Adenosine is a neuromodulator that has been involved in aging and neurodegenerative diseases as Alzheimer’s disease (AD). In the present work, we analyzed the possible modulation of purine metabolites, 5’nucleotidase (5′NT) and adenosine deaminase (ADA) activities, and adenosine monophosphate (AMP)-activated protein kinase (AMPK) and its phosphorylated form during aging in the cerebral cortex. Three murine models were used: senescence-accelerated mouse-resistant 1 (SAMR1, normal senescence), senescence-accelerated mouse-prone 8 (SAMP8, a model of AD), and the wild-type C57BL/6J (model of aging) mice strains. Glutamate and excitatory amino acid transporter 2 (EAAT2) levels were also measured in these animals. HPLC, Western blotting, and enzymatic activity evaluation were performed to this aim. 5′-Nucleotidase (5′NT) activity was decreased at six months and recovered at 12 months in SAMP8 while opposite effects were observed in SAMR1 at the same age, and no changes in C57BL/6J mice. ADA activity significantly decreased from 3 to 12 months in the SAMR1 mice strain, while a significant decrease from 6 to 12 months was observed in the SAMP8 mice strain. Regarding purine metabolites, xanthine and guanosine levels were increased at six months in SAMR1 without significant differences in SAMP8 mice. In C57BL/6J mice, inosine and xanthine were increased, while adenosine decreased, from 4 to 24 months. The AMPK level was decreased at six months in SAMP8 without significant changes nor in SAMR1 or C57BL/6J strains. Glutamate and EAAT2 levels were also modulated during aging. Our data show a different modulation of adenosine metabolism participants in the cerebral cortex of these animal models. Interestingly, the main differences between SAMR1 and SAMP8 mice were found at six months of age, SAMP8 being the most affected strain. As SAMP8 is an AD model, results suggest that adenosinergic metabolism is involved in the neurodegeneration of AD. Full article
(This article belongs to the Special Issue Dissecting the Purinergic Signaling Puzzle)
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20 pages, 4263 KiB  
Article
Cross-Talk between P2X and NMDA Receptors
by Larry Rodriguez, Catherine Yi, Cameron Chu, Quentin Duriez, Sharyse Watanabe, Megan Ryu, Brandon Reyes, Liana Asatryan, Eric Boué-Grabot and Daryl Davies
Int. J. Mol. Sci. 2020, 21(19), 7187; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197187 - 29 Sep 2020
Cited by 14 | Viewed by 3041
Abstract
Purinergic P2X receptors (P2X) are ATP-gated ion channels widely expressed in the CNS. While the direct contribution of P2X to synaptic transmission is uncertain, P2X reportedly affect N-methyl-D-aspartate receptor (NMDAR) activity, which has given rise to competing theories on the role of P2X [...] Read more.
Purinergic P2X receptors (P2X) are ATP-gated ion channels widely expressed in the CNS. While the direct contribution of P2X to synaptic transmission is uncertain, P2X reportedly affect N-methyl-D-aspartate receptor (NMDAR) activity, which has given rise to competing theories on the role of P2X in the modulation of synapses. However, P2X have also been shown to participate in receptor cross-talk: an interaction where one receptor (e.g., P2X2) directly influences the activity of another (e.g., nicotinic, 5-HT3 or GABA receptors). In this study, we tested for interactions between P2X2 or P2X4 and NMDARs. Using two-electrode voltage-clamp electrophysiology experiments in Xenopus laevis oocytes, we demonstrate that both P2X2 and P2X4 interact with NMDARs in an inhibited manner. When investigating the molecular domains responsible for this phenomenon, we found that the P2X2 c-terminus (CT) could interfere with both P2X2 and P2X4 interactions with NMDARs. We also report that 11 distal CT residues on the P2X4 facilitate the P2X4–NMDAR interaction, and that a peptide consisting of these P2X4 CT residues (11C) can disrupt the interaction between NMDARs and P2X2 or P2X4. Collectively, these results provide new evidence for the modulatory nature of P2X2 and P2X4, suggesting they might play a more nuanced role in the CNS. Full article
(This article belongs to the Special Issue Dissecting the Purinergic Signaling Puzzle)
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11 pages, 2392 KiB  
Article
Ecto-Nucleotide Triphosphate Diphosphohydrolase-2 (NTPDase2) Deletion Increases Acetaminophen-Induced Hepatotoxicity
by Linda Feldbrügge, Katrin Splith, Ines Kämmerer, Sandra Richter, Anna Riddermann, Santiago Andres Ortiz Galindo, Felix Krenzien, Tobias Müller, Eva Csizmadia, Johann Pratschke, Simon C. Robson and Moritz Schmelzle
Int. J. Mol. Sci. 2020, 21(17), 5998; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21175998 - 20 Aug 2020
Cited by 3 | Viewed by 2726
Abstract
Ecto-nucleotidase triphosphate diphosphohydrolase-2 (NTPDase2) is an ecto-enzyme that is expressed on portal fibroblasts in the liver that modulates P2 receptor signaling by regulating local concentrations of extracellular ATP and ADP. NTPDase2 has protective properties in liver fibrosis and may impact bile duct epithelial [...] Read more.
Ecto-nucleotidase triphosphate diphosphohydrolase-2 (NTPDase2) is an ecto-enzyme that is expressed on portal fibroblasts in the liver that modulates P2 receptor signaling by regulating local concentrations of extracellular ATP and ADP. NTPDase2 has protective properties in liver fibrosis and may impact bile duct epithelial turnover. Here, we study the role of NTPDase2 in acute liver injury using an experimental model of acetaminophen (APAP) intoxication in mice with global deletion of NTPDase2. Acute liver toxicity was caused by administration of acetaminophen in wild type (WT) and NTPDase2-deficient (Entpd2 null) mice. The extent of liver injury was compared by histology and serum alanine transaminase (ALT). Markers of inflammation, regeneration and fibrosis were determined by qPCR). We found that Entpd2 expression is significantly upregulated after acetaminophen-induced hepatotoxicity. Entpd2 null mice showed significantly more necrosis and higher serum ALT compared to WT. Hepatic expression of IL-6 and PDGF-B are higher in Entpd2 null mice. Our data suggest inducible and protective roles of portal fibroblast-expressed NTPDase2 in acute necrotizing liver injury. Further studies should investigate the relevance of these purinergic pathways in hepatic periportal and sinusoidal biology as such advances in understanding might provide possible therapeutic targets. Full article
(This article belongs to the Special Issue Dissecting the Purinergic Signaling Puzzle)
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14 pages, 1591 KiB  
Article
Adenosine A2A and A3 Receptors Are Able to Interact with Each Other. A Further Piece in the Puzzle of Adenosine Receptor-Mediated Signaling
by Alejandro Lillo, Eva Martínez-Pinilla, Irene Reyes-Resina, Gemma Navarro and Rafael Franco
Int. J. Mol. Sci. 2020, 21(14), 5070; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145070 - 17 Jul 2020
Cited by 13 | Viewed by 3912
Abstract
The aim of this paper was to check the possible interaction of two of the four purinergic P1 receptors, the A2A and the A3. Discovery of the A2A–A3 receptor complex was achieved by means of immunocytochemistry and [...] Read more.
The aim of this paper was to check the possible interaction of two of the four purinergic P1 receptors, the A2A and the A3. Discovery of the A2A–A3 receptor complex was achieved by means of immunocytochemistry and of bioluminescence resonance energy transfer. The functional properties and heteromer print identification were addressed by combining binding and signaling assays. The physiological role of the novel heteromer is to provide a differential signaling depending on the pre-coupling to signal transduction components and/or on the concentration of the endogenous agonist. The main feature was that the heteromeric context led to a marked decrease of the signaling originating at A3 receptors. Interestingly from a therapeutic point of view, A2A receptor antagonists overrode the blockade, thus allowing A3 receptor-mediated signaling. The A2A–A3 receptor heteromer print was detected in primary cortical neurons. These and previous results suggest that all four adenosine receptors may interact with each other. Therefore, each adenosine receptor could form heteromers with distinct properties, expanding the signaling outputs derived from the binding of adenosine to its cognate receptors. Full article
(This article belongs to the Special Issue Dissecting the Purinergic Signaling Puzzle)
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17 pages, 2565 KiB  
Article
Signaling Through Purinergic Receptor P2Y2 Enhances Macrophage IL-1β Production
by Gonzalo de la Rosa, Ana I. Gómez, María C. Baños and Pablo Pelegrín
Int. J. Mol. Sci. 2020, 21(13), 4686; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134686 - 30 Jun 2020
Cited by 15 | Viewed by 3014
Abstract
The release of nucleotides during necrosis or apoptosis has been described to have both proinflammatory and anti-inflammatory effect on the surrounding cells. Here we describe how low concentrations of UTP and ATP applied during macrophage priming enhance IL-1β production when subsequently the NLRP3 [...] Read more.
The release of nucleotides during necrosis or apoptosis has been described to have both proinflammatory and anti-inflammatory effect on the surrounding cells. Here we describe how low concentrations of UTP and ATP applied during macrophage priming enhance IL-1β production when subsequently the NLRP3 inflammasome is activated in murine resident peritoneal macrophages. Deficiency or pharmacological inhibition of the purinergic receptor P2Y2 reverted the increase of IL-1β release induced by nucleotides. IL-1β increase was found dependent on the expression of Il1b gene and probably involving JNK activity. On the contrary, nucleotides decreased the production of a different proinflammatory cytokines such as TNF-α. These results suggest that nucleotides could shape the response of macrophages to obtain a unique proinflammatory signature that might be relevant in unrevealing specific inflammatory conditions. Full article
(This article belongs to the Special Issue Dissecting the Purinergic Signaling Puzzle)
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15 pages, 926 KiB  
Article
Adenosine Deaminase as a Biomarker of Tenofovir Mediated Inflammation in Naïve HIV Patients
by Francisco Miguel Conesa-Buendía, Patricia Llamas-Granda, Patricia Atencio, Alfonso Cabello, Miguel Górgolas, Raquel Largo, Gabriel Herrero-Beaumont and Aránzazu Mediero
Int. J. Mol. Sci. 2020, 21(10), 3590; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103590 - 19 May 2020
Cited by 4 | Viewed by 3526
Abstract
Plasma levels of adenosine deaminase (ADA), an enzyme that deaminates adenosine to inosine, are increased during inflammation. An increase in ADA activity occurs with lower human immunodeficiency virus (HIV) viral load and higher CD4+ T cell counts. We aimed to investigate the [...] Read more.
Plasma levels of adenosine deaminase (ADA), an enzyme that deaminates adenosine to inosine, are increased during inflammation. An increase in ADA activity occurs with lower human immunodeficiency virus (HIV) viral load and higher CD4+ T cell counts. We aimed to investigate the role of plasma ADA as a biomarker of inflammation in treatment-naïve HIV patients who received tenofovir or another nucleoside analog for comparison. Ninety-two treatment-naïve patients were included in the study and grouped by treatment, i.e., tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) or Triumeq. ADA activity was measured in plasma and cytokines were analyzed by MILLIPLEX® MAP-Luminex® Technology. Plasma concentration of monocytes and neutrophils was measured at 0, 3, and 12 months post-treatment. Treatment-naïve HIV patients had increased ADA concentrations (over 15 U/L) that decreased after treatment with TAF and Triumeq, though this did not occur in TDF-treated patients. However, all groups exhibited a pro-inflammatory systemic profile at 12 months of treatment. Plasma GM-CSF levels decreased after 12 months of treatment in the TDF group, with a concomitant decrease in blood monocyte count, and a negative correlation with ADA values was found. In conclusion, ADA levels may be modulated by antiretroviral therapy in HIV patients, possibly affecting inflammatory status. Full article
(This article belongs to the Special Issue Dissecting the Purinergic Signaling Puzzle)
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20 pages, 3859 KiB  
Article
Abnormal Upregulation of GPR17 Receptor Contributes to Oligodendrocyte Dysfunction in SOD1 G93A Mice
by Elisabetta Bonfanti, Tiziana Bonifacino, Stefano Raffaele, Marco Milanese, Erica Morgante, Giambattista Bonanno, Maria P. Abbracchio and Marta Fumagalli
Int. J. Mol. Sci. 2020, 21(7), 2395; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072395 - 31 Mar 2020
Cited by 35 | Viewed by 7678
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor neurons (MN). Importantly, MN degeneration is intimately linked to oligodendrocyte dysfunction and impaired capacity of oligodendrocyte precursor cells (OPCs) to regenerate the myelin sheath enwrapping and protecting neuronal axons. [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor neurons (MN). Importantly, MN degeneration is intimately linked to oligodendrocyte dysfunction and impaired capacity of oligodendrocyte precursor cells (OPCs) to regenerate the myelin sheath enwrapping and protecting neuronal axons. Thus, improving OPC reparative abilities represents an innovative approach to counteract MN loss. A pivotal regulator of OPC maturation is the P2Y-like G protein-coupled receptor 17 (GPR17), whose role in ALS has never been investigated. In other models of neurodegeneration, an abnormal increase of GPR17 has been invariably associated to myelin defects and its pharmacological manipulation succeeded in restoring endogenous remyelination. Here, we analyzed GPR17 alterations in the SOD1G93A ALS mouse model and assessed in vitro whether this receptor could be targeted to correct oligodendrocyte alterations. Western-blot and immunohistochemical analyses showed that GPR17 protein levels are significantly increased in spinal cord of ALS mice at pre-symptomatic stage; this alteration is exacerbated at late symptomatic phases. Concomitantly, mature oligodendrocytes degenerate and are not successfully replaced. Moreover, OPCs isolated from spinal cord of SOD1G93A mice display defective differentiation compared to control cells, which is rescued by treatment with the GPR17 antagonist montelukast. These data open novel therapeutic perspectives for ALS management. Full article
(This article belongs to the Special Issue Dissecting the Purinergic Signaling Puzzle)
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Review

Jump to: Editorial, Research

18 pages, 12943 KiB  
Review
Purinergic Regulation of Endothelial Barrier Function
by Muhammad Aslam, Dursun Gündüz, Christian Troidl, Jacqueline Heger, Christian W. Hamm and Rainer Schulz
Int. J. Mol. Sci. 2021, 22(3), 1207; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031207 - 26 Jan 2021
Cited by 20 | Viewed by 3172
Abstract
Increased vascular permeability is a hallmark of several cardiovascular anomalies, including ischaemia/reperfusion injury and inflammation. During both ischaemia/reperfusion and inflammation, massive amounts of various nucleotides, particularly adenosine 5′-triphosphate (ATP) and adenosine, are released that can induce a plethora of signalling pathways via activation [...] Read more.
Increased vascular permeability is a hallmark of several cardiovascular anomalies, including ischaemia/reperfusion injury and inflammation. During both ischaemia/reperfusion and inflammation, massive amounts of various nucleotides, particularly adenosine 5′-triphosphate (ATP) and adenosine, are released that can induce a plethora of signalling pathways via activation of several purinergic receptors and may affect endothelial barrier properties. The nature of the effects on endothelial barrier function may depend on the prevalence and type of purinergic receptors activated in a particular tissue. In this review, we discuss the influence of the activation of various purinergic receptors and downstream signalling pathways on vascular permeability during pathological conditions. Full article
(This article belongs to the Special Issue Dissecting the Purinergic Signaling Puzzle)
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18 pages, 887 KiB  
Review
P2 Receptors in Cardiac Myocyte Pathophysiology and Mechanotransduction
by Sun-Hee Woo and Tran Nguyet Trinh
Int. J. Mol. Sci. 2021, 22(1), 251; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010251 - 29 Dec 2020
Cited by 7 | Viewed by 3558
Abstract
ATP is a major energy source in the mammalian cells, but it is an extracellular chemical messenger acting on P2 purinergic receptors. A line of evidence has shown that ATP is released from many different types of cells including neurons, endothelial cells, and [...] Read more.
ATP is a major energy source in the mammalian cells, but it is an extracellular chemical messenger acting on P2 purinergic receptors. A line of evidence has shown that ATP is released from many different types of cells including neurons, endothelial cells, and muscle cells. In this review, we described the distribution of P2 receptor subtypes in the cardiac cells and their physiological and pathological roles in the heart. So far, the effects of external application of ATP or its analogues, and those of UTP on cardiac contractility and rhythm have been reported. In addition, specific genetic alterations and pharmacological agonists and antagonists have been adopted to discover specific roles of P2 receptor subtypes including P2X4-, P2X7-, P2Y2- and P2Y6-receptors in cardiac cells under physiological and pathological conditions. Accumulated data suggest that P2X4 receptors may play a beneficial role in cardiac muscle function, and that P2Y2- and P2Y6-receptors can induce cardiac fibrosis. Recent evidence further demonstrates P2Y1 receptor and P2X4 receptor as important mechanical signaling molecules to alter membrane potential and Ca2+ signaling in atrial myocytes and their uneven expression profile between right and left atrium. Full article
(This article belongs to the Special Issue Dissecting the Purinergic Signaling Puzzle)
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21 pages, 30304 KiB  
Review
Purinergic Signaling in Pancreas—From Physiology to Therapeutic Strategies in Pancreatic Cancer
by Ivana Novak, Haoran Yu, Lara Magni and Ganga Deshar
Int. J. Mol. Sci. 2020, 21(22), 8781; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228781 - 20 Nov 2020
Cited by 12 | Viewed by 3520
Abstract
The purinergic signaling has an important role in regulating pancreatic exocrine secretion. The exocrine pancreas is also a site of one of the most serious cancer forms, the pancreatic ductal adenocarcinoma (PDAC). Here, we explore how the network of purinergic and adenosine receptors, [...] Read more.
The purinergic signaling has an important role in regulating pancreatic exocrine secretion. The exocrine pancreas is also a site of one of the most serious cancer forms, the pancreatic ductal adenocarcinoma (PDAC). Here, we explore how the network of purinergic and adenosine receptors, as well as ecto-nucleotidases regulate normal pancreatic cells and various cells within the pancreatic tumor microenvironment. In particular, we focus on the P2X7 receptor, P2Y2 and P2Y12 receptors, as well as A2 receptors and ecto-nucleotidases CD39 and CD73. Recent studies indicate that targeting one or more of these candidates could present new therapeutic approaches to treat pancreatic cancer. In pancreatic cancer, as much as possible of normal pancreatic function should be preserved, and therefore physiology of purinergic signaling in pancreas needs to be considered. Full article
(This article belongs to the Special Issue Dissecting the Purinergic Signaling Puzzle)
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15 pages, 749 KiB  
Review
Modulatory Roles of ATP and Adenosine in Cholinergic Neuromuscular Transmission
by Ayrat U. Ziganshin, Adel E. Khairullin, Charles H. V. Hoyle and Sergey N. Grishin
Int. J. Mol. Sci. 2020, 21(17), 6423; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176423 - 03 Sep 2020
Cited by 19 | Viewed by 3467
Abstract
A review of the data on the modulatory action of adenosine 5’-triphosphate (ATP), the main co-transmitter with acetylcholine, and adenosine, the final ATP metabolite in the synaptic cleft, on neuromuscular transmission is presented. The effects of these endogenous modulators on pre- and post-synaptic [...] Read more.
A review of the data on the modulatory action of adenosine 5’-triphosphate (ATP), the main co-transmitter with acetylcholine, and adenosine, the final ATP metabolite in the synaptic cleft, on neuromuscular transmission is presented. The effects of these endogenous modulators on pre- and post-synaptic processes are discussed. The contribution of purines to the processes of quantal and non-quantal secretion of acetylcholine into the synaptic cleft, as well as the influence of the postsynaptic effects of ATP and adenosine on the functioning of cholinergic receptors, are evaluated. As usual, the P2-receptor-mediated influence is minimal under physiological conditions, but it becomes very important in some pathophysiological situations such as hypothermia, stress, or ischemia. There are some data demonstrating the same in neuromuscular transmission. It is suggested that the role of endogenous purines is primarily to provide a safety factor for the efficiency of cholinergic neuromuscular transmission. Full article
(This article belongs to the Special Issue Dissecting the Purinergic Signaling Puzzle)
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14 pages, 1990 KiB  
Review
Role of P2Y Receptors in Platelet Extracellular Vesicle Release
by Aleksandra Gąsecka, Sylwester Rogula, Ceren Eyileten, Marek Postuła, Miłosz J. Jaguszewski, Janusz Kochman, Tomasz Mazurek, Rienk Nieuwland and Krzysztof J. Filipiak
Int. J. Mol. Sci. 2020, 21(17), 6065; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176065 - 23 Aug 2020
Cited by 20 | Viewed by 3276
Abstract
Platelet extracellular vesicles (PEVs) are potential new biomarkers of platelet activation which may allow us to predict and/or diagnose developing coronary thrombosis before myocardial necrosis occurs. The P2Y1 and P2Y12 receptors play a key role in platelet activation and aggregation. Whereas the P2Y1 [...] Read more.
Platelet extracellular vesicles (PEVs) are potential new biomarkers of platelet activation which may allow us to predict and/or diagnose developing coronary thrombosis before myocardial necrosis occurs. The P2Y1 and P2Y12 receptors play a key role in platelet activation and aggregation. Whereas the P2Y1 antagonists are at the preclinical stage, at present, the P2Y12 antagonists are the most effective treatment strategy to prevent stent thrombosis after percutaneous coronary intervention. Despite an increasing number of publications on PEVs, the mechanisms underlying their formation, including the role of purinergic receptors in this process, remain an active research field. Here, we outline the clinical relevance of PEVs in cardiovascular disease, summarize the role and downstream signalling of P2Y receptors in platelet activation, and discuss the available evidence regarding their role in PEV formation. Full article
(This article belongs to the Special Issue Dissecting the Purinergic Signaling Puzzle)
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16 pages, 624 KiB  
Review
Contribution of P2X4 Receptors to CNS Function and Pathophysiology
by Alejandro Montilla, Gilda Paloma Mata, Carlos Matute and Maria Domercq
Int. J. Mol. Sci. 2020, 21(15), 5562; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155562 - 03 Aug 2020
Cited by 42 | Viewed by 4425
Abstract
The release and extracellular action of ATP are a widespread mechanism for cell-to-cell communication in living organisms through activation of P2X and P2Y receptors expressed at the cell surface of most tissues, including the nervous system. Among ionototropic receptors, P2X4 receptors have emerged [...] Read more.
The release and extracellular action of ATP are a widespread mechanism for cell-to-cell communication in living organisms through activation of P2X and P2Y receptors expressed at the cell surface of most tissues, including the nervous system. Among ionototropic receptors, P2X4 receptors have emerged in the last decade as a potential target for CNS disorders such as epilepsy, ischemia, chronic pain, anxiety, multiple sclerosis and neurodegenerative diseases. However, the role of P2X4 receptor in each pathology ranges from beneficial to detrimental, although the mechanisms are still mostly unknown. P2X4 is expressed at low levels in CNS cells including neurons and glial cells. In normal conditions, P2X4 activation contributes to synaptic transmission and synaptic plasticity. Importantly, one of the genes present in the transcriptional program of myeloid cell activation is P2X4. Microglial P2X4 upregulation, the P2X4+ state of microglia, seems to be common in most acute and chronic neurodegenerative diseases associated with inflammation. In this review, we summarize knowledge about the role of P2X4 receptors in the CNS physiology and discuss potential pitfalls and open questions about the therapeutic potential of blocking or potentiation of P2X4 for different pathologies. Full article
(This article belongs to the Special Issue Dissecting the Purinergic Signaling Puzzle)
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22 pages, 952 KiB  
Review
Resolving the Ionotropic P2X4 Receptor Mystery Points towards a New Therapeutic Target for Cardiovascular Diseases
by Bruno Bragança and Paulo Correia-de-Sá
Int. J. Mol. Sci. 2020, 21(14), 5005; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145005 - 15 Jul 2020
Cited by 16 | Viewed by 3677
Abstract
Adenosine triphosphate (ATP) is a primordial versatile autacoid that changes its role from an intracellular energy saver to a signaling molecule once released to the extracellular milieu. Extracellular ATP and its adenosine metabolite are the main activators of the P2 and P1 purinoceptor [...] Read more.
Adenosine triphosphate (ATP) is a primordial versatile autacoid that changes its role from an intracellular energy saver to a signaling molecule once released to the extracellular milieu. Extracellular ATP and its adenosine metabolite are the main activators of the P2 and P1 purinoceptor families, respectively. Mounting evidence suggests that the ionotropic P2X4 receptor (P2X4R) plays pivotal roles in the regulation of the cardiovascular system, yet further therapeutic advances have been hampered by the lack of selective P2X4R agonists. In this review, we provide the state of the art of the P2X4R activity in the cardiovascular system. We also discuss the role of P2X4R activation in kidney and lungs vis a vis their interplay to control cardiovascular functions and dysfunctions, including putative adverse effects emerging from P2X4R activation. Gathering this information may prompt further development of selective P2X4R agonists and its translation to the clinical practice. Full article
(This article belongs to the Special Issue Dissecting the Purinergic Signaling Puzzle)
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