International Journal of Molecular Sciences

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Open AccessEditorial

Purinergic Signalling in Physiology and Pathophysiology

by Ronald Sluyter

Int. J. Mol. Sci. 2023, 24(11), 9196; https://doi.org/10.3390/ijms24119196 - 24 May 2023

Viewed by 1276

Abstract

Since its inception by the late Geoffrey Burnstock in the early 1970s [...] Full article

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

Research

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14 pages, 2219 KiB

Open AccessArticle

Knockout of Purinergic P2Y₆ Receptor Fails to Improve Liver Injury and Inflammation in Non-Alcoholic Steatohepatitis

by Kazuhiro Nishiyama, Kohei Ariyoshi, Akiyuki Nishimura, Yuri Kato, Xinya Mi, Hitoshi Kurose, Sang Geon Kim and Motohiro Nishida

Int. J. Mol. Sci. 2023, 24(4), 3800; https://doi.org/10.3390/ijms24043800 - 14 Feb 2023

Cited by 3 | Viewed by 2572

Abstract

Nonalcoholic steatohepatitis (NASH) is a disease that progresses from nonalcoholic fatty liver (NAFL) and which is characterized by inflammation and fibrosis. The purinergic P2Y₆ receptor (P2Y₆R) is a pro-inflammatory G_q/G₁₂ family protein-coupled receptor and reportedly contributes to [...] Read more.

Nonalcoholic steatohepatitis (NASH) is a disease that progresses from nonalcoholic fatty liver (NAFL) and which is characterized by inflammation and fibrosis. The purinergic P2Y₆ receptor (P2Y₆R) is a pro-inflammatory G_q/G₁₂ family protein-coupled receptor and reportedly contributes to intestinal inflammation and cardiovascular fibrosis, but its role in liver pathogenesis is unknown. Human genomics data analysis revealed that the liver P2Y₆R mRNA expression level is increased during the progression from NAFL to NASH, which positively correlates with inductions of C-C motif chemokine 2 (CCL2) and collagen type I α1 chain (Col1a1) mRNAs. Therefore, we examined the impact of P2Y₆R functional deficiency in mice crossed with a NASH model using a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Feeding CDAHFD for 6 weeks markedly increased P2Y₆R expression level in mouse liver, which was positively correlated with CCL2 mRNA induction. Unexpectedly, the CDAHFD treatment for 6 weeks increased liver weights with severe steatosis in both wild-type (WT) and P2Y₆R knockout (KO) mice, while the disease marker levels such as serum AST and liver CCL2 mRNA in CDAHFD-treated P2Y₆R KO mice were rather aggravated compared with those of CDAHFD-treated WT mice. Thus, P2Y₆R may not contribute to the progression of liver injury, despite increased expression in NASH liver. Full article

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

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22 pages, 4706 KiB

Open AccessArticle

Identification of Leukocyte Surface P2X7 as a Biomarker Associated with Alzheimer’s Disease

by Yihan Li, Xin Huang, Christopher Fowler, Yen Y. Lim, Simon M. Laws, Noel Faux, James D. Doecke, Brett Trounson, Kelly Pertile, Rebecca Rumble, Vincent Doré, Victor L. Villemagne, Christopher C. Rowe, James S. Wiley, Paul Maruff, Colin L. Masters and Ben J. Gu

Int. J. Mol. Sci. 2022, 23(14), 7867; https://doi.org/10.3390/ijms23147867 - 17 Jul 2022

Cited by 9 | Viewed by 2797

Abstract

Alzheimer’s disease (AD) has shown altered immune responses in the periphery. We studied P2X7 (a proinflammatory receptor and a scavenger receptor) and two integrins, CD11b and CD11c, on the surface of circulating leukocytes and analysed their associations with Aβ-PET, brain atrophy, neuropsychological assessments, [...] Read more.

Alzheimer’s disease (AD) has shown altered immune responses in the periphery. We studied P2X7 (a proinflammatory receptor and a scavenger receptor) and two integrins, CD11b and CD11c, on the surface of circulating leukocytes and analysed their associations with Aβ-PET, brain atrophy, neuropsychological assessments, and cerebrospinal fluid (CSF) biomarkers. Total 287 age-matched, sex-balanced participants were recruited in a discovery cohort and two validation cohorts through the AIBL study and studied using tri-colour flow cytometry. Our results demonstrated reduced expressions of P2X7, CD11b, and CD11c on leukocytes, particularly monocytes, in Aβ +ve cases compared with Aβ −ve controls. P2X7 and integrin downregulation was observed at pre-clinical stage of AD and stayed low throughout disease course. We further constructed a polygenic risk score (PRS) model based on 12 P2RX7 risk alleles to assess the genetic impact on P2X7 function in AIBL and ADNI cohorts. No significant association was identified between the P2RX7 gene and AD, indicating that P2X7 downregulation in AD is likely caused by environmental changes rather than genetic factors. In conclusion, the downregulation of P2X7 and integrins at pre-clinical stage of AD indicates altered pro-inflammatory responses, phagocytic functions, and migrating capabilities of circulating monocytes in early AD pathogenesis. Our study not only improves our understanding of peripheral immune involvement in early stage of AD but also provides more insights into novel biomarker development, diagnosis, and prognosis of AD. Full article

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

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21 pages, 7684 KiB

Open AccessArticle

Hypercholesterolemia Negatively Regulates P2X7-Induced Cellular Function in CD4⁺ and CD8⁺ T-Cell Subsets from B6 Mice Fed a High-Fat Diet

by Tom Hutteau-Hamel, Amine Mellouk, Nicolas Trainel, Anne-Marie Cassard and Pierre Bobé

Int. J. Mol. Sci. 2022, 23(12), 6730; https://doi.org/10.3390/ijms23126730 - 16 Jun 2022

Cited by 2 | Viewed by 2025

Abstract

We have previously showed that plasma membrane cholesterol and GM1 ganglioside content are responsible for the opposite sensitivity of mouse leukemic T cells to ATP. We also reported that the sensitivity of CD4⁺ and CD8⁺ T cells to ATP depends on [...] Read more.

We have previously showed that plasma membrane cholesterol and GM1 ganglioside content are responsible for the opposite sensitivity of mouse leukemic T cells to ATP. We also reported that the sensitivity of CD4⁺ and CD8⁺ T cells to ATP depends on their stage of differentiation. Here, we show that CD4⁺ and CD8⁺ T cells from B6 mice express different levels of membrane GM1 and P2X7 but similar levels of cholesterol. Thus, in CD4⁺ T cells, membrane cholesterol content negatively correlated with ATP/P2X7-induced CD62L shedding but positively correlated with pore formation, phosphatidylserine externalization, and cell death. By contrast, in CD8⁺ T cells, cholesterol, GM1, and P2X7 levels negatively correlated with all these ATP/P2X7-induced cellular responses. The relationship between cholesterol and P2X7-induced cellular responses was confirmed by modulating cholesterol levels either ex vivo or through a high-fat diet. Membrane cholesterol enrichment ex vivo led to a significant reduction in all P2X7-induced cellular responses in T cells. Importantly, diet-induced hypercholesterolemia in B6 mice was also associated with decreased sensitivity to ATP in CD4⁺ and CD8⁺ T cells, highlighting the relationship between cholesterol intake and the amplitudes of P2X7-induced cellular responses in T cells. Full article

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

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18 pages, 7999 KiB

Open AccessArticle

Adenosine Receptor A2B Negatively Regulates Cell Migration in Ovarian Carcinoma Cells

by Anaí del Rocío Campos-Contreras, Adriana González-Gallardo, Mauricio Díaz-Muñoz and Francisco G. Vázquez-Cuevas

Int. J. Mol. Sci. 2022, 23(9), 4585; https://doi.org/10.3390/ijms23094585 - 21 Apr 2022

Cited by 6 | Viewed by 2417

Abstract

The purinergic system is fundamental in the tumor microenvironment, since it regulates tumor cell interactions with the immune system, as well as growth and differentiation in autocrine-paracrine responses. Here, we investigated the role of the adenosine A2B receptor (A2BR) in ovarian carcinoma-derived cells’ [...] Read more.

The purinergic system is fundamental in the tumor microenvironment, since it regulates tumor cell interactions with the immune system, as well as growth and differentiation in autocrine-paracrine responses. Here, we investigated the role of the adenosine A2B receptor (A2BR) in ovarian carcinoma-derived cells’ (OCDC) properties. From public databases, we documented that high A2BR expression is associated with a better prognostic outcome in ovarian cancer patients. In vitro experiments were performed on SKOV-3 cell line to understand how A2BR regulates the carcinoma cell phenotype associated with cell migration. RT-PCR and Western blotting revealed that the ADORA2B transcript (coding for A2BR) and A2BR were expressed in SKOV-3 cells. Stimulation with BAY-606583, an A2BR agonist, induced ERK1/2 phosphorylation, which was abolished by the antagonist PSB-603. Pharmacological activation of A2BR reduced cell migration and actin stress fibers; in agreement, A2BR knockdown increased migration and enhanced actin stress fiber expression. Furthermore, the expression of E-cadherin, an epithelial marker, increased in BAY-606583-treated cells. Finally, cDNA microarrays revealed the pathways mediating the effects of A2BR activation on SKOV-3 cells. Our results showed that A2BR contributed to maintaining an epithelial-like phenotype in OCDC and highlighted this purinergic receptor as a potential biomarker. Full article

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

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24 pages, 14577 KiB

Open AccessArticle

High, in Contrast to Low Levels of Acute Stress Induce Depressive-like Behavior by Involving Astrocytic, in Addition to Microglial P2X7 Receptors in the Rodent Hippocampus

by Ya-Fei Zhao, Wen-Jing Ren, Ying Zhang, Jin-Rong He, Hai-Yan Yin, Yang Liao, Patrizia Rubini, Jan M. Deussing, Alexei Verkhratsky, Zeng-Qiang Yuan, Peter Illes and Yong Tang

Int. J. Mol. Sci. 2022, 23(3), 1904; https://doi.org/10.3390/ijms23031904 - 8 Feb 2022

Cited by 19 | Viewed by 3909

Abstract

Extracellular adenosine 5′-triphosphate (ATP) in the brain is suggested to be an etiological factor of major depressive disorder (MDD). It has been assumed that stress-released ATP stimulates P2X7 receptors (Rs) at the microglia, thereby causing neuroinflammation; however, other central nervous system (CNS) cell [...] Read more.

Extracellular adenosine 5′-triphosphate (ATP) in the brain is suggested to be an etiological factor of major depressive disorder (MDD). It has been assumed that stress-released ATP stimulates P2X7 receptors (Rs) at the microglia, thereby causing neuroinflammation; however, other central nervous system (CNS) cell types such as astrocytes also possess P2X7Rs. In order to elucidate the possible involvement of the MDD-relevant hippocampal astrocytes in the development of a depressive-like state, we used various behavioral tests (tail suspension test [TST], forced swim test [FST], restraint stress, inescapable foot shock, unpredictable chronic mild stress [UCMS]), as well as fluorescence immunohistochemistry, and patch-clamp electrophysiology in wild-type (WT) and genetically manipulated rodents. The TST and FST resulted in learned helplessness manifested as a prolongation of the immobility time, while inescapable foot shock caused lower sucrose consumption as a sign of anhedonia. We confirmed the participation of P2X7Rs in the development of the depressive-like behaviors in all forms of acute (TST, FST, foot shock) and chronic stress (UCMS) in the rodent models used. Further, pharmacological agonists and antagonists acted in a different manner in rats and mice due to their diverse potencies at the respective receptor orthologs. In hippocampal slices of mice and rats, only foot shock increased the current responses to locally applied dibenzoyl-ATP (Bz-ATP) in CA1 astrocytes; in contrast, TST and restraint depressed these responses. Following stressful stimuli, immunohistochemistry demonstrated an increased co-localization of P2X7Rs with a microglial marker, but no change in co-localization with an astroglial marker. Pharmacological damage to the microglia and astroglia has proven the significance of the microglia for mediating all types of depression-like behavioral reactions, while the astroglia participated only in reactions induced by strong stressors, such as foot shock. Because, in addition to acute stressors, their chronic counterparts induce a depressive-like state in rodents via P2X7R activation, we suggest that our data may have relevance for the etiology of MDD in humans. Full article

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

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Review

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17 pages, 1300 KiB

Open AccessReview

A Systematic Review of the Role of Purinergic Signalling Pathway in the Treatment of COVID-19

by Vitoria Guero Korb, Iago Carvalho Schultz, Liziane Raquel Beckenkamp and Márcia Rosângela Wink

Int. J. Mol. Sci. 2023, 24(9), 7865; https://doi.org/10.3390/ijms24097865 - 26 Apr 2023

Cited by 5 | Viewed by 2432

Abstract

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global health concern. Three years since its origin, despite the approval of vaccines and specific treatments against this new coronavirus, there are still high rates [...] Read more.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global health concern. Three years since its origin, despite the approval of vaccines and specific treatments against this new coronavirus, there are still high rates of infection, hospitalization, and mortality in some countries. COVID-19 is characterised by a high inflammatory state and coagulation disturbances that may be linked to purinergic signalling molecules such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine (ADO), and purinergic receptors (P1 and P2). These nucleotides/nucleosides play important roles in cellular processes, such as immunomodulation, blood clot formation, and vasodilation, which are affected during SARS-CoV-2 infection. Therefore, drugs targeting this purinergic pathway, currently used for other pathologies, are being evaluated in preclinical and clinical trials for COVID-19. In this review, we focus on the potential of these drugs to control the release, degradation, and reuptake of these extracellular nucleotides and nucleosides to treat COVID-19. Drugs targeting the P1 receptors could have therapeutic efficacy due to their capacity to modulate the cytokine storm and the immune response. Those acting in P2X7, which is linked to NLRP3 inflammasome activation, are also valuable candidates as they can reduce the release of pro-inflammatory cytokines. However, according to the available preclinical and clinical data, the most promising medications to be used for COVID-19 treatment are those that modulate platelets behaviour and blood coagulation factors, mainly through the P2Y12 receptor. Full article

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

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14 pages, 1142 KiB

Open AccessReview

Purine Metabolism Dysfunctions: Experimental Methods of Detection and Diagnostic Potential

by Arrigo F. G. Cicero, Federica Fogacci, Valentina Di Micoli, Cristina Angeloni, Marina Giovannini and Claudio Borghi

Int. J. Mol. Sci. 2023, 24(8), 7027; https://doi.org/10.3390/ijms24087027 - 10 Apr 2023

Cited by 21 | Viewed by 4228

Abstract

Purines, such as adenine and guanine, perform several important functions in the cell. They are found in nucleic acids; are structural components of some coenzymes, including NADH and coenzyme A; and have a crucial role in the modulation of energy metabolism and signal [...] Read more.

Purines, such as adenine and guanine, perform several important functions in the cell. They are found in nucleic acids; are structural components of some coenzymes, including NADH and coenzyme A; and have a crucial role in the modulation of energy metabolism and signal transduction. Moreover, purines have been shown to play an important role in the physiology of platelets, muscles, and neurotransmission. All cells require a balanced number of purines for growth, proliferation, and survival. Under physiological conditions, enzymes involved in purines metabolism maintain a balanced ratio between their synthesis and degradation in the cell. In humans, the final product of purine catabolism is uric acid, while most other mammals possess the enzyme uricase that converts uric acid to allantoin, which can be easily eliminated with urine. During the last decades, hyperuricemia has been associated with a number of human extra-articular diseases (in particular, the cardiovascular ones) and their clinical severity. In this review, we go through the methods of investigation of purine metabolism dysfunctions, looking at the functionality of xanthine oxidoreductase and the formation of catabolites in urine and saliva. Finally, we discuss how these molecules can be used as markers of oxidative stress. Full article

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

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14 pages, 1072 KiB

Open AccessReview

CD73: Friend or Foe in Lung Injury

by Xiu-Min Hu, Nan-Rui Shi, Ji-Zhou Zhang, Yan-Qin Zuo, Xin Wang, Ya-Fei Zhao and Jia-Si Wu

Int. J. Mol. Sci. 2023, 24(6), 5545; https://doi.org/10.3390/ijms24065545 - 14 Mar 2023

Cited by 3 | Viewed by 3008

Abstract

Ecto-5′-nucleotidase (CD73) plays a strategic role in calibrating the magnitude and chemical nature of purinergic signals that are delivered to immune cells. Its primary function is to convert extracellular ATP to adenosine in concert with ectonucleoside triphosphate diphosphohydrolase-1 (CD39) in normal tissues to [...] Read more.

Ecto-5′-nucleotidase (CD73) plays a strategic role in calibrating the magnitude and chemical nature of purinergic signals that are delivered to immune cells. Its primary function is to convert extracellular ATP to adenosine in concert with ectonucleoside triphosphate diphosphohydrolase-1 (CD39) in normal tissues to limit an excessive immune response in many pathophysiological events, such as lung injury induced by a variety of contributing factors. Multiple lines of evidence suggest that the location of CD73, in proximity to adenosine receptor subtypes, indirectly determines its positive or negative effect in a variety of organs and tissues and that its action is affected by the transfer of nucleoside to subtype-specific adenosine receptors. Nonetheless, the bidirectional nature of CD73 as an emerging immune checkpoint in the pathogenesis of lung injury is still unknown. In this review, we explore the relationship between CD73 and the onset and progression of lung injury, highlighting the potential value of this molecule as a drug target for the treatment of pulmonary disease. Full article

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

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11 pages, 1559 KiB

Open AccessReview

Delineating Purinergic Signaling in Drosophila

by Cinzia Volonté, Francesca Alberti, Giuseppe Vitale and Francesco Liguori

Int. J. Mol. Sci. 2022, 23(23), 15196; https://doi.org/10.3390/ijms232315196 - 2 Dec 2022

Cited by 1 | Viewed by 2069

Abstract

Simplistic models can aid in discovering what is important in the context of normal and pathological behavior. First recognized as a genetic model more than 100 years ago, to date, fruit flies (Drosophila melanogaster) still remain an astonishingly good laboratory stand-in [...] Read more.

Simplistic models can aid in discovering what is important in the context of normal and pathological behavior. First recognized as a genetic model more than 100 years ago, to date, fruit flies (Drosophila melanogaster) still remain an astonishingly good laboratory stand-in for scientists to study development and physiology and to investigate the molecular mechanisms of human diseases. This is because fruit flies indeed represent a simplistic model. Furthermore, about 75% of human disease-related genes have their counterparts in the Drosophila genome, added to the fact that fruit flies are inexpensive and extremely easy to maintain, being invertebrates and, moreover, lacking any ethical concern issues. Purinergic signaling is, by definition, mediated by extracellular purinergic ligands, among which ATP represents the prototype molecule. A key feature that has progressively emerged when dissecting the purinergic mechanisms is the multilayer and dynamic nature of the signaling sustained by purinergic ligands. Indeed, these last are sequentially metabolized by several different ectonucleotidases, which generate the ligands that simultaneously activate several different purinergic receptors. Since significant purinergic actions have also been described in Drosophila, the aim of the present work is to provide a comprehensive picture of the purinergic events occurring in fruit flies. Full article

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

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17 pages, 1830 KiB

Open AccessReview

Purinergic Signalling in the Cochlea

by Srdjan M. Vlajkovic and Peter R. Thorne

Int. J. Mol. Sci. 2022, 23(23), 14874; https://doi.org/10.3390/ijms232314874 - 28 Nov 2022

Cited by 11 | Viewed by 6736

Abstract

The mammalian cochlea is the sensory organ of hearing with a delicate, highly organised structure that supports unique operating mechanisms. ATP release from the secretory tissues of the cochlear lateral wall (stria vascularis) triggers numerous physiological responses by activating P2 receptors in sensory, [...] Read more.

The mammalian cochlea is the sensory organ of hearing with a delicate, highly organised structure that supports unique operating mechanisms. ATP release from the secretory tissues of the cochlear lateral wall (stria vascularis) triggers numerous physiological responses by activating P2 receptors in sensory, supporting and neural tissues. Two families of P2 receptors, ATP-gated ion channels (P2X receptors) and G protein-coupled P2Y receptors, activate intracellular signalling pathways that regulate cochlear development, homeostasis, sensory transduction, auditory neurotransmission and response to stress. Of particular interest is a purinergic hearing adaptation, which reflects the critical role of the P2X₂ receptor in adaptive cochlear response to elevated sound levels. Other P2 receptors are involved in the maturation of neural processes and frequency selectivity refinement in the developing cochlea. Extracellular ATP signalling is regulated by a family of surface-located enzymes collectively known as “ectonucleotidases” that hydrolyse ATP to adenosine. Adenosine is a constitutive cell metabolite with an established role in tissue protection and regeneration. The differential activation of A₁ and A_2A adenosine receptors defines the cochlear response to injury caused by oxidative stress, inflammation, and activation of apoptotic pathways. A₁ receptor agonism, A_2A receptor antagonism, and increasing adenosine levels in cochlear fluids all represent promising therapeutic tools for cochlear rescue from injury and prevention of hearing loss. Full article

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

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20 pages, 1308 KiB

Open AccessReview

Adenosine, Schizophrenia and Cancer: Does the Purinergic System Offer a Pathway to Treatment?

by Abdul-Rizaq Hamoud, Karen Bach, Ojal Kakrecha, Nicholas Henkel, Xiaojun Wu, Robert E. McCullumsmith and Sinead M. O’Donovan

Int. J. Mol. Sci. 2022, 23(19), 11835; https://doi.org/10.3390/ijms231911835 - 5 Oct 2022

Cited by 6 | Viewed by 3531

Abstract

For over a century, a complex relationship between schizophrenia diagnosis and development of many cancers has been observed. Findings from epidemiological studies are mixed, with reports of increased, reduced, or no difference in cancer incidence in schizophrenia patients. However, as risk factors for [...] Read more.

For over a century, a complex relationship between schizophrenia diagnosis and development of many cancers has been observed. Findings from epidemiological studies are mixed, with reports of increased, reduced, or no difference in cancer incidence in schizophrenia patients. However, as risk factors for cancer, including elevated smoking rates and substance abuse, are commonly associated with this patient population, it is surprising that cancer incidence is not higher. Various factors may account for the proposed reduction in cancer incidence rates including pathophysiological changes associated with disease. Perturbations of the adenosine system are hypothesized to contribute to the neurobiology of schizophrenia. Conversely, hyperfunction of the adenosine system is found in the tumor microenvironment in cancer and targeting the adenosine system therapeutically is a promising area of research in this disease. We outline the current biochemical and pharmacological evidence for hypofunction of the adenosine system in schizophrenia, and the role of increased adenosine metabolism in the tumor microenvironment. In the context of the relatively limited literature on this patient population, we discuss whether hypofunction of this system in schizophrenia, may counteract the immunosuppressive role of adenosine in the tumor microenvironment. We also highlight the importance of studies examining the adenosine system in this subset of patients for the potential insight they may offer into these complex disorders. Full article

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

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22 pages, 1844 KiB

Open AccessReview

Alternatively Spliced Isoforms of the P2X7 Receptor: Structure, Function and Disease Associations

by Sophie K. F. De Salis, Lanxin Li, Zheng Chen, Kam Wa Lam, Kristen K. Skarratt, Thomas Balle and Stephen J. Fuller

Int. J. Mol. Sci. 2022, 23(15), 8174; https://doi.org/10.3390/ijms23158174 - 25 Jul 2022

Cited by 15 | Viewed by 3074

Abstract

The P2X7 receptor (P2X7R) is an ATP-gated membrane ion channel that is expressed by multiple cell types. Following activation by extracellular ATP, the P2X7R mediates a broad range of cellular responses including cytokine and chemokine release, cell survival and differentiation, the activation of [...] Read more.

The P2X7 receptor (P2X7R) is an ATP-gated membrane ion channel that is expressed by multiple cell types. Following activation by extracellular ATP, the P2X7R mediates a broad range of cellular responses including cytokine and chemokine release, cell survival and differentiation, the activation of transcription factors, and apoptosis. The P2X7R is made up of three P2X7 subunits that contain specific domains essential for the receptor’s varied functions. Alternative splicing produces P2X7 isoforms that exclude one or more of these domains and assemble in combinations that alter P2X7R function. The modification of the structure and function of the P2X7R may adversely affect cellular responses to carcinogens and pathogens, and alternatively spliced (AS) P2X7 isoforms have been associated with several cancers. This review summarizes recent advances in understanding the structure and function of AS P2X7 isoforms and their associations with cancer and potential role in modulating the inflammatory response. Full article

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

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22 pages, 2399 KiB

Open AccessReview

Purinergic Signaling in Oral Tissues

by Mariachiara Zuccarini, Patricia Giuliani, Maurizio Ronci, Francesco Caciagli, Vanni Caruso, Renata Ciccarelli and Patrizia Di Iorio

Int. J. Mol. Sci. 2022, 23(14), 7790; https://doi.org/10.3390/ijms23147790 - 14 Jul 2022

Cited by 4 | Viewed by 3001

Abstract

The role of the purinergic signal has been extensively investigated in many tissues and related organs, including the central and peripheral nervous systems as well as the gastrointestinal, cardiovascular, respiratory, renal, and immune systems. Less attention has been paid to the influence of [...] Read more.

The role of the purinergic signal has been extensively investigated in many tissues and related organs, including the central and peripheral nervous systems as well as the gastrointestinal, cardiovascular, respiratory, renal, and immune systems. Less attention has been paid to the influence of purines in the oral cavity, which is the first part of the digestive apparatus and also acts as the body’s first antimicrobial barrier. In this review, evidence is provided of the presence and possible physiological role of the purinergic system in the different structures forming the oral cavity including teeth, tongue, hard palate, and soft palate with their annexes such as taste buds, salivary glands, and nervous fibers innervating the oral structures. We also report findings on the involvement of the purinergic signal in pathological conditions affecting the oral apparatus such as Sjögren’s syndrome or following irradiation for the treatment of head and neck cancer, and the use of experimental drugs interfering with the purine system to improve bone healing after damage. Further investigations are required to translate the results obtained so far into the clinical setting in order to pave the way for a wider application of purine-based treatments in oral diseases. Full article

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

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16 pages, 7887 KiB

Open AccessReview

The P2X4 Receptor: Cellular and Molecular Characteristics of a Promising Neuroinflammatory Target

by Reece Andrew Sophocleous, Lezanne Ooi and Ronald Sluyter

Int. J. Mol. Sci. 2022, 23(10), 5739; https://doi.org/10.3390/ijms23105739 - 20 May 2022

Cited by 18 | Viewed by 4228

Abstract

The adenosine 5′-triphosphate-gated P2X4 receptor channel is a promising target in neuroinflammatory disorders, but the ability to effectively target these receptors in models of neuroinflammation has presented a constant challenge. As such, the exact role of P2X4 receptors and their cell signalling mechanisms [...] Read more.

The adenosine 5′-triphosphate-gated P2X4 receptor channel is a promising target in neuroinflammatory disorders, but the ability to effectively target these receptors in models of neuroinflammation has presented a constant challenge. As such, the exact role of P2X4 receptors and their cell signalling mechanisms in human physiology and pathophysiology still requires further elucidation. To this end, research into the molecular mechanisms of P2X4 receptor activation, modulation, and inhibition has continued to gain momentum in an attempt to further describe the role of P2X4 receptors in neuroinflammation and other disease settings. Here we provide an overview of the current understanding of the P2X4 receptor, including its expression and function in cells involved in neuroinflammatory signalling. We discuss the pharmacology of P2X4 receptors and provide an overview of P2X4-targeting molecules, including agonists, positive allosteric modulators, and antagonists. Finally, we discuss the use of P2X4 receptor modulators and antagonists in models of neuroinflammatory cell signalling and disease. Full article

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

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