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Purinergic Signalling in Physiology and Pathophysiology 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 February 2025 | Viewed by 10621

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Prof. Dr. Ronald Sluyter

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Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
Interests: cellular immunology; cancer immunology; transplant immunology; neuroimmunology; purinergic signalling; P2X7 receptors
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Dear Colleagues,

Extracellular nucleotides and nucleosides are essential autocrine and paracrine signalling molecules. The action of these extracellular molecules is mediated by the activation of cell-surface receptors comprising P2X ion channels, as well as P2Y and adenosine G-protein-coupled receptors. Furthermore, the concentrations of extracellular nucleotides and nucleosides are regulated by various ectoenzymes and nucleotide/nucleoside release and transport mechanisms. Collectively, these molecules and processes form a network of cellular communication termed purinergic signalling. This network occurs in a wide range of cells and tissues, and plays important roles in physiology and pathophysiology in various species.

The aim of this Special Issue is to provide current examples and overviews of the various roles of purinergic signalling in a range of physiological and pathophysiological contexts. Original articles and reviews relating to specific purinergic receptors, ectoenzymes or nucleotide/nucleoside release and transport mechanisms, as well as those providing holistic views of purinergic signalling, are welcomed.

Prof. Dr. Ronald Sluyter
Guest Editor

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Keywords

purinergic signalling
purinome
ATP
ADP
UTP
UDP
UDP-glucose
adenosine
P2X receptors
P2Y receptors
P1 receptors
adenosine receptors
ectoenzymes
nucleotidases
nucleotide release
nucleoside release
nucleotide transport
nucleoside transport

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Purinergic Signalling in Physiology and Pathophysiology in International Journal of Molecular Sciences (15 articles)

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Research

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16 pages, 1607 KiB

Open AccessArticle

P2Y₁ and P2Y₁₂ Receptors Mediate Aggregation of Dog and Cat Platelets: A Comparison to Human Platelets

by Reece A. Sophocleous, Stephen J. Curtis, Belinda L. Curtis, Lezanne Ooi and Ronald Sluyter

Int. J. Mol. Sci. 2025, 26(3), 1206; https://doi.org/10.3390/ijms26031206 - 30 Jan 2025

Viewed by 348

Abstract

Thrombosis is one of the most prevalent and serious health issues amongst humans. A key component of thrombotic events is the activation and aggregation of platelets, of which the P2Y₁ and P2Y₁₂ receptors play a crucial role in this process. Despite a breadth of knowledge on thrombosis and its mechanisms and treatment in various disorders in humans, there is less of an understanding of the expression and exact role of these receptors in companion animals such as dogs and cats. Therefore, this study aimed to investigate P2Y₁ and P2Y₁₂ receptors on dog and cat platelets in platelet-rich plasma and compare them to human platelets. Immunoblotting revealed the presence of P2Y₁ and P2Y₁₂ receptor proteins on dog and cat platelets, although relative amounts of each receptor appeared to contrast those of human platelets, with increased amounts of P2Y₁ compared to P2Y₁₂ receptors in dogs and cats. Using a modified 384-well plate aggregation assay, designed for use with small volumes, the human P2Y₁ and P2Y₁₂ receptor agonists adenosine 5′-diphosphate and 2-methylthio-adenosine 5′-diphosphate caused aggregation of dog and cat platelets. This aggregation was near-completely inhibited by the selective P2Y₁₂ antagonist ticagrelor. Aggregation of dog and cat platelets was partly inhibited by the human P2Y₁ receptor antagonist MRS2179. The agonist and antagonist responses in dog and cat platelets were like those of human platelets. In contrast, the aggregation of dog platelets in the absence of added nucleotides was two-fold greater than that of cats and humans. This study indicates that platelets of cats and dogs possess functional P2Y₁ and P2Y₁₂ receptors that can be inhibited by human antagonists. The data presented suggest differing roles or responses of the platelet P2Y receptors in dogs and cats compared to humans but also highlight the potential of using currently available P2Y₁ or P2Y₁₂ antiplatelet drugs such as ticagrelor for the treatment of thrombosis in these companion animals. Full article

(This article belongs to the Special Issue Purinergic Signalling in Physiology and Pathophysiology 2.0)

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26 pages, 9841 KiB

Open AccessArticle

Prostaglandins Differentially Regulate the Constitutive and Mechanosensitive Release of Soluble Nucleotidases in the Urinary Bladder Mucosa

by Alejandro Gutierrez Cruz, Mahsa Borhani Peikani, Tori D. Beaulac and Violeta N. Mutafova-Yambolieva

Int. J. Mol. Sci. 2025, 26(1), 131; https://doi.org/10.3390/ijms26010131 - 27 Dec 2024

Viewed by 462

Abstract

The urothelium and lamina propria (LP) contribute to sensations of bladder fullness by releasing multiple mediators, including prostaglandins (PGs) and adenosine 5′-triphosphate (ATP), that activate or modulate functions of cells throughout the bladder wall. Mediators that are simultaneously released in response to bladder distention likely influence each other’s mechanisms of release and action. This study investigated whether PGs could alter the extracellular hydrolysis of ATP by soluble nucleotidases (s-NTDs) released in the LP of nondistended or distended bladders. Using an ex vivo murine detrusor-free bladder model to access the LP during bladder filling and a sensitive HPLC-FLD detection methodology, we evaluated the decrease in ATP and the increase in adenosine 5′-diphosphate (ADP), adenosine 5′-monophosphate (AMP), and adenosine by s-NTDs released in the LP. Endogenous PGE₂ increased the spontaneous but not the distention-induced release of s-NTD via EP2 and EP3 prostanoid receptors, whereas exogenous PGE₂ increased the spontaneous s-NTD release via EP3, EP4, and FP receptors and the distention-induced s-NTD release via EP1-4 and FP receptors. Endogenous PGF_2α, PGD₂, and PGI₂ did not change the s-NTD release. Exogenous PGD₂ increased the spontaneous s-NTD release via DP2 receptors and the distention-induced s-NTD release via DP1 and DP2 receptors. Exogenous PGF_2α increased the spontaneous but not the distention-induced release of s-NTD via FP receptors. It is possible that higher concentrations of PGE₂, PGF_2α, and PGD₂ (as expected in inflammation, bladder pain syndrome, or overactive bladder) potentiate the release of s-NTDs and the consecutive degradation of ATP as a safeguard mechanism to prevent the development of excessive bladder excitability and overactivity by high amounts of extracellular ATP. Full article

(This article belongs to the Special Issue Purinergic Signalling in Physiology and Pathophysiology 2.0)

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17 pages, 2047 KiB

Open AccessArticle

P2X7 Receptor-Induced Human Mast Cell Degranulation Is Enhanced by Interleukin 33

by Barbora Salcman, Rajia Bahri, Peter W. West, Chiara Tontini, Karen Affleck and Silvia Bulfone-Paus

Int. J. Mol. Sci. 2024, 25(3), 1730; https://doi.org/10.3390/ijms25031730 - 31 Jan 2024

Cited by 2 | Viewed by 1702

Abstract

MCs are tissue-resident immune cells that strategically reside in barrier organs and respond effectively to a wide range of stimuli, such as IL-33, a mediator released upon epithelial damage. Adenosine triphosphate (ATP) accumulates at sites of tissue injury and is known to modulate MC activities. This study investigated how an inflammatory tissue environment rich in IL-33 modulates the ATP-mediated activation of MCs. Human primary MCs primed with IL-33 displayed a strongly increased response to ATP but not ADP. This resulted in increased degranulation, IL-8 release, and pERK1/2 signalling. Such effects are unique to IL-33 stimulation and not shared by the epithelial alarmin, TSLP. MC exposure to IL-33 also increased membrane expression of purinergic and ATP-binding P2X receptors. The use of selective P2X receptor inhibitors identified P2X7 receptor as the key mediator of the enhanced ATP-induced ERK1/2 signalling and degranulation in IL-33-primed MCs. Whilst the inhibition of P2X1 and P2X4 receptors had no effect on MC degranulation, inhibiting these receptors together with P2X7 resulted in further decreased MC-mediated degranulation. These data therefore point toward the potential mechanisms by which IL-33 contributes to the modulation of ATP-mediated activation in human MCs. Full article

(This article belongs to the Special Issue Purinergic Signalling in Physiology and Pathophysiology 2.0)

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13 pages, 2733 KiB

Open AccessArticle

Elevated CD39+T-Regulatory Cells and Reduced Levels of Adenosine Indicate a Role for Tolerogenic Signals in the Progression from Moderate to Severe COVID-19

by Alaa Elsaghir, Ehsan M. W. El-Sabaa, Asmaa M. Zahran, Sahar A. Mandour, Eman H. Salama, Sahar Aboulfotuh, Reham M. El-Morshedy, Stefania Tocci, Ahmed Mohamed Mandour, Wael Esmat Ali, Lobna Abdel-Wahid, Ibrahim M. Sayed and Mohamed A. El-Mokhtar

Int. J. Mol. Sci. 2023, 24(24), 17614; https://doi.org/10.3390/ijms242417614 - 18 Dec 2023

Cited by 3 | Viewed by 1879

Abstract

Viral infections trigger inflammation by controlling ATP release. CD39 ectoenzymes hydrolyze ATP/ADP to AMP, which is converted by CD73 into anti-inflammatory adenosine (ADO). ADO is an anti-inflammatory and immunosuppressant molecule which can enhance viral persistence and severity. The CD39-CD73-adenosine axis contributes to the immunosuppressive T-reg microenvironment and may affect COVID-19 disease progression. Here, we investigated the link between CD39 expression, mostly on T-regs, and levels of CD73, adenosine, and adenosine receptors with COVID-19 severity and progression. Our study included 73 hospitalized COVID-19 patients, of which 33 were moderately affected and 40 suffered from severe infection. A flow cytometric analysis was used to analyze the frequency of T-regulatory cells (T-regs), CD39+ T-regs, and CD39+CD4+ T-cells. Plasma concentrations of adenosine, IL-10, and TGF-β were quantified via an ELISA. An RT-qPCR was used to analyze the gene expression of CD73 and adenosine receptors (A1, A2A, A2B, and A3). T-reg cells were higher in COVID-19 patients compared to healthy controls (7.4 ± 0.79 vs. 2.4 ± 0.28; p < 0.0001). Patients also had a higher frequency of the CD39+ T-reg subset. In addition, patients who suffered from a severe form of the disease had higher CD39+ T-regs compared with moderately infected patients. CD39+CD4+ T cells were increased in patients compared to the control group. An analysis of serum adenosine levels showed a marked decrease in their levels in patients, particularly those suffering from severe illness. However, this was paralleled with a marked decline in the expression levels of CD73. IL-10 and TGF-β levels were higher in COVID-19; in addition, their values were also higher in the severe group. In conclusion, there are distinct immunological alterations in CD39+ lymphocyte subsets and a dysregulation in the adenosine signaling pathway in COVID-19 patients which may contribute to immune dysfunction and disease progression. Understanding these immunological alterations in the different immune cell subsets and adenosine signaling provides valuable insights into the pathogenesis of the disease and may contribute to the development of novel therapeutic approaches targeting specific immune mechanisms. Full article

(This article belongs to the Special Issue Purinergic Signalling in Physiology and Pathophysiology 2.0)

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18 pages, 5338 KiB

Open AccessArticle

A Regulator Role for the ATP-Binding Cassette Subfamily C Member 6 Transporter in HepG2 Cells: Effect on the Dynamics of Cell–Cell and Cell–Matrix Interactions

by Ilenia Matera, Rocchina Miglionico, Vittorio Abruzzese, Giovanna Marchese, Giovanna Maria Ventola, Maria Antonietta Castiglione Morelli, Faustino Bisaccia and Angela Ostuni

Int. J. Mol. Sci. 2023, 24(22), 16391; https://doi.org/10.3390/ijms242216391 - 16 Nov 2023

Cited by 2 | Viewed by 1778

Abstract

There is growing evidence that various ATP-binding cassette (ABC) transporters contribute to the growth and development of tumors, but relatively little is known about how the ABC transporter family behaves in hepatocellular carcinoma (HCC), one of the most common cancers worldwide. Cellular model studies have shown that ABCC6, which belongs to the ABC subfamily C (ABCC), plays a role in the cytoskeleton rearrangement and migration of HepG2 hepatocarcinoma cells, thus highlighting its role in cancer biology. Deep knowledge on the molecular mechanisms underlying the observed results could provide therapeutic insights into the tumors in which ABCC6 is modulated. In this study, differential expression levels of mRNA transcripts between ABCC6-silenced HepG2 and control groups were measured, and subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed. Real-Time PCR and Western blot analyses confirmed bioinformatics; functional studies support the molecular mechanisms underlying the observed effects. The results provide valuable information on the dysregulation of fundamental cellular processes, such as the focal adhesion pathway, which allowed us to obtain detailed information on the active role that the down-regulation of ABCC6 could play in the biology of liver tumors, as it is involved not only in cell migration but also in cell adhesion and invasion. Full article

(This article belongs to the Special Issue Purinergic Signalling in Physiology and Pathophysiology 2.0)

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14 pages, 2028 KiB

Open AccessArticle

Low Pretreatment CD4⁺:CD8⁺ T Cell Ratios and CD39⁺CD73⁺CD19⁺ B Cell Proportions Are Associated with Improved Relapse-Free Survival in Head and Neck Squamous Cell Carcinoma

by Ross J. Turner, Thomas V. Guy, Nicholas J. Geraghty, Ashleigh Splitt, Debbie Watson, Daniel Brungs, Martin G. Carolan, Andrew A. Miller, Jeremiah F. de Leon, Morteza Aghmesheh and Ronald Sluyter

Int. J. Mol. Sci. 2023, 24(16), 12538; https://doi.org/10.3390/ijms241612538 - 8 Aug 2023

Cited by 2 | Viewed by 1876

Abstract

The ectonucleotidases CD39 and CD73 are present on immune cells and play important roles in cancer progression by suppressing antitumour immunity. As such, CD39 and CD73 on peripheral blood mononuclear cells (PBMCs) are emerging as potential biomarkers to predict disease outcomes and treatment responses in cancer patients. This study aimed to examine T and B cells, including CD39 and CD73 expressing subsets, by flow cytometry in PBMCs from 28 patients with head and neck squamous cell carcinoma (HNSCC) and to assess the correlation with the treatment modality, human papillomavirus (HPV) status, and relapse-free survival (RFS). The PBMCs were examined pre-, mid-, and post-radiotherapy with concurrent cisplatin chemotherapy or anti-epidermal growth factor receptor antibody (cetuximab) therapy. Combination radiotherapy caused changes to T and B cell populations, including CD39 and CD73 expressing subsets, but no such differences were observed between concurrent chemotherapy and cetuximab. Pretreatment PBMCs from HPV⁺ patients contained increased proportions of CD39⁻CD73⁻CD4⁺ T cells and reduced proportions of CD39^−/+CD73⁺CD4⁺ T cells compared to the equivalent cells from HPV⁻ patients. Notably, the pretreatment CD4⁺:CD8⁺ T cell ratios and CD39⁺CD73⁺CD19⁺ B cell proportions below the respective cohort medians corresponded with an improved RFS. Collectively, this study supports the notion that CD39 and CD73 may contribute to disease outcomes in HNSCC patients and may assist as biomarkers, either alone or as part of immune signatures, in HNSCC. Further studies of CD39 and CD73 on PBMCs from larger cohorts of HNSCC patients are warranted. Full article

(This article belongs to the Special Issue Purinergic Signalling in Physiology and Pathophysiology 2.0)

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28 pages, 1146 KiB

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Purinergic Signaling in Non-Parenchymal Liver Cells

by Esperanza Mata-Martínez, María Guadalupe Ramírez-Ledesma, Genaro Vázquez-Victorio, Rolando Hernández-Muñoz, Mauricio Díaz-Muñoz and Francisco G. Vázquez-Cuevas

Int. J. Mol. Sci. 2024, 25(17), 9447; https://doi.org/10.3390/ijms25179447 - 30 Aug 2024

Viewed by 1313

Abstract

Purinergic signaling has emerged as an important paracrine–autocrine intercellular system that regulates physiological and pathological processes in practically all organs of the body. Although this system has been thoroughly defined since the nineties, recent research has made substantial advances regarding its role in aspects of liver physiology. However, most studies have mainly targeted the entire organ, 70% of which is made up of parenchymal cells or hepatocytes. Because of its physiological role, the liver is exposed to toxic metabolites, such as xenobiotics, drugs, and fatty acids, as well as to pathogens such as viruses and bacteria. Under injury conditions, all cell types within the liver undergo adaptive changes. In this context, the concentration of extracellular ATP has the potential to increase dramatically. Indeed, this purinergic response has not been studied in sufficient detail in non-parenchymal liver cells. In the present review, we systematize the physiopathological adaptations related to the purinergic system in chronic liver diseases of non-parenchymal liver cells, such as hepatic stellate cells, Kupffer cells, sinusoidal endothelial cells, and cholangiocytes. The role played by non-parenchymal liver cells in these circumstances will undoubtedly be strategic in understanding the regenerative activities that support the viability of this organ under stressful conditions. Full article

(This article belongs to the Special Issue Purinergic Signalling in Physiology and Pathophysiology 2.0)

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