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Science Signaling Oct 2023Lung ischemia-reperfusion injury (IRI), characterized by inflammation, vascular permeability, and lung edema, is the major cause of primary graft dysfunction after lung...
Lung ischemia-reperfusion injury (IRI), characterized by inflammation, vascular permeability, and lung edema, is the major cause of primary graft dysfunction after lung transplantation. Here, we investigated the cellular mechanisms underlying lung IR-induced activation of endothelial TRPV4 channels, which play a central role in lung edema and dysfunction after IR. In a left lung hilar-ligation model of IRI in mice, we found that lung IRI increased the efflux of ATP through pannexin 1 (Panx1) channels at the endothelial cell (EC) membrane. Elevated extracellular ATP activated Ca influx through endothelial TRPV4 channels downstream of purinergic P2Y2 receptor (P2Y2R) signaling. P2Y2R-dependent activation of TRPV4 channels was also observed in human and mouse pulmonary microvascular endothelium in ex vivo and in vitro models of IR. Endothelium-specific deletion of P2Y2R, TRPV4, or Panx1 in mice substantially prevented lung IRI-induced activation of endothelial TRPV4 channels and lung edema, inflammation, and dysfunction. These results identify endothelial P2Y2R as a mediator of the pathological sequelae of IRI in the lung and show that disruption of the endothelial Panx1-P2Y2R-TRPV4 signaling pathway could be a promising therapeutic strategy for preventing lung IRI after transplantation.
Topics: Humans; Animals; Mice; TRPV Cation Channels; Receptors, Purinergic P2Y2; Lung; Reperfusion Injury; Endothelial Cells; Inflammation; Adenosine Triphosphate; Edema; Nerve Tissue Proteins; Connexins
PubMed: 37874885
DOI: 10.1126/scisignal.adg1553 -
Neuropharmacology Nov 2023Uridine 5'-diphosphoglucose (UDP-G) as a preferential agonist, but also other UDP-sugars, such as UDP galactose, function as extracellular signaling molecules under... (Review)
Review
Uridine 5'-diphosphoglucose (UDP-G) as a preferential agonist, but also other UDP-sugars, such as UDP galactose, function as extracellular signaling molecules under conditions of cell injury and apoptosis. Consequently, UDP-G is regarded to function as a damage-associated molecular pattern (DAMP), regulating immune responses. UDP-G promotes neutrophil recruitment, leading to the release of pro-inflammatory chemokines. As a potent endogenous agonist with the highest affinity for the P2Y receptor (R), it accomplishes an exclusive relationship between P2YRs in regulating inflammation via cyclic adenosine monophosphate (cAMP), nod-like receptor protein 3 (NLRP3) inflammasome, mitogen-activated protein kinases (MAPKs), and signal transducer and activator of transcription 1 (STAT1) pathways. In this review, we initially present a brief introduction into the expression and function of P2YRs in combination with UDP-G. Subsequently, we summarize emerging roles of UDP-G/P2YR signaling pathways that modulate inflammatory responses in diverse systems, and discuss the underlying mechanisms of P2YR activation in inflammation-related diseases. Moreover, we also refer to the applications as well as effects of novel agonists/antagonists of P2YRs in inflammatory conditions. In conclusion, due to the role of the P2YR in the immune system and inflammatory pathways, it may represent a novel target for anti-inflammatory therapy.
Topics: Humans; Receptors, Purinergic P2; Uridine Diphosphate Glucose; Uridine Diphosphate Sugars; Inflammation; Glucose
PubMed: 37423482
DOI: 10.1016/j.neuropharm.2023.109655 -
Biomedicine & Pharmacotherapy =... Sep 2023Adenosine is an endogenous nucleoside that regulates many physiological and pathological processes. It is derived from either the intracellular or extracellular... (Review)
Review
Adenosine is an endogenous nucleoside that regulates many physiological and pathological processes. It is derived from either the intracellular or extracellular dephosphorylation of adenosine triphosphate and interacts with cell-surface G-protein-coupled receptors. Adenosine plays a substantial role in protecting against cell damage in areas of increased tissue metabolism and preventing organ dysfunction in pathological states. Targeting adenosine metabolism and receptor signaling may be an effective therapeutic approach for human diseases, including cardiovascular and central nervous system disorders, rheumatoid arthritis, asthma, renal diseases, and cancer. Several lines of evidence have shown that many drugs exert their beneficial effects by modulating adenosine signaling pathways but this knowledge urgently needs to be summarized, and most importantly, actualized. The present review collects pharmaceuticals and pharmacological or diagnostic tools that target adenosine signaling in their primary or secondary mode of action. We overviewed FDA-approved drugs as well as those currently being studied in clinical trials. Among them are already used in clinic A2A adenosine receptor modulators like istradefylline or regadenoson, but also plenty of anti-platelet, anti-inflammatory, or immunosuppressive, and anti-cancer drugs. On the other hand, we investigated dozens of specific adenosine pathway regulators that are tested in clinical trials to treat human infectious and noninfectious diseases. In conclusion, targeting purinergic signaling represents a great therapeutic challenge. The actual knowledge of the involvement of adenosinergic signaling as part of the mechanism of action of old drugs has open a path not only for drug-repurposing but also for new therapeutic strategies.
Topics: Humans; Adenosine; Adenosine Triphosphate; Receptors, Purinergic P1; Cell Membrane; Signal Transduction
PubMed: 37506580
DOI: 10.1016/j.biopha.2023.115184 -
Purinergic Signalling Sep 2023Receptor agonists and antagonists and other modulators of purinergic signalling have potential as novel therapeutics for a broad range of diseases and conditions. This...
Receptor agonists and antagonists and other modulators of purinergic signalling have potential as novel therapeutics for a broad range of diseases and conditions. This special issue focuses on compounds or approaches that are either in clinical trials or headed in that direction. It is intended to serve as an up-to-date description of selected efforts to discover and develop new small molecular purinergic drugs.
Topics: Receptors, Purinergic P2X; Biological Products; Signal Transduction
PubMed: 37676356
DOI: 10.1007/s11302-023-09964-9 -
International Journal of Molecular... Aug 2023Pain represents an international burden and a major socio-economic public health problem. New findings, detailed in this review, suggest that adenosine plays a... (Review)
Review
Pain represents an international burden and a major socio-economic public health problem. New findings, detailed in this review, suggest that adenosine plays a significant role in neuropathic and inflammatory pain, by acting on its metabotropic adenosine receptors (AAR, AAR, AAR, AAR). Adenosine receptor ligands have a practical translational potential based on the favorable efficacy and safety profiles that emerged from clinical research on various agonists and antagonists for different pathologies. The present review collects the latest studies on selected adenosine receptor ligands in different pain models. Here, we also covered the many hypothesized pathways and the role of newly synthesized allosteric adenosine receptor modulators. This review aims to present a summary of recent research on adenosine receptors as prospective therapeutic targets for a range of pain-related disorders.
Topics: Humans; Ligands; Analgesics; Pain; Adenosine; Receptors, Purinergic P1
PubMed: 37685963
DOI: 10.3390/ijms241713160 -
The Journal of Biological Chemistry Apr 2024Extracellular ATP activates P2 purinergic receptors. Whether purinergic signaling is functionally coupled to cellular senescence is largely unknown. We find that...
Extracellular ATP activates P2 purinergic receptors. Whether purinergic signaling is functionally coupled to cellular senescence is largely unknown. We find that oxidative stress induced release of ATP and caused senescence in human lung fibroblasts. Inhibition of P2 receptors limited oxidative stress-induced senescence, while stimulation with exogenous ATP promoted premature senescence. Pharmacological inhibition of P2Y11 receptor (P2Y11R) inhibited premature senescence induced by either oxidative stress or ATP, while stimulation with a P2Y11R agonist was sufficient to induce cellular senescence. Our data show that both extracellular ATP and a P2Y11R agonist induced calcium (Ca) release from the endoplasmic reticulum (ER) and that either inhibition of phospholipase C or intracellular Ca chelation impaired ATP-induced senescence. We also find that Ca that was released from the ER, following ATP-mediated activation of phospholipase C, entered mitochondria in a manner dependent on P2Y11R activation. Once in mitochondria, excessive Ca promoted the production of reactive oxygen species in a P2Y11R-dependent fashion, which drove development of premature senescence of lung fibroblasts. Finally, we show that conditioned medium derived from senescent lung fibroblasts, which were induced to senesce through the activation of ATP/P2Y11R-mediated signaling, promoted the proliferation of triple-negative breast cancer cells and their tumorigenic potential by secreting amphiregulin. Our study identifies the existence of a novel purinergic signaling pathway that links extracellular ATP to the development of a protumorigenic premature senescent phenotype in lung fibroblasts that is dependent on P2Y11R activation and ER-to-mitochondria calcium signaling.
Topics: Humans; Adenosine Triphosphate; Calcium; Calcium Signaling; Cellular Senescence; Endoplasmic Reticulum; Fibroblasts; Lung; Mitochondria; Oxidative Stress; Reactive Oxygen Species; Receptors, Purinergic P2; Signal Transduction; Type C Phospholipases; Cell Line; Cell Proliferation
PubMed: 38460941
DOI: 10.1016/j.jbc.2024.107145 -
Neuropharmacology Sep 2023Ionotropic receptors are ligand-gated ion channels triggering fast neurotransmitter responses. Among them, P2X and 5-HT receptors have been shown to physically interact... (Review)
Review
Ionotropic receptors are ligand-gated ion channels triggering fast neurotransmitter responses. Among them, P2X and 5-HT receptors have been shown to physically interact each other and functionally inducing cross inhibitory responses. Nevertheless, despite the importance of P2X4 and 5-HT receptors that mediate for example neuropathic pain and psychosis respectively, complementary evidence has recently started to move forward in the understanding of this interaction. In this review, we discuss current evidence supporting the mechanism of crosstalking between both receptors, from the structural to the transduction pathway level. We expect this work may guide the design of further experiments to obtain a comprehensive view for the neuropharmacological role of these interacting receptors. This article is part of the Special Issue on "The receptor-receptor interaction as a new target for therapy".
Topics: Receptors, Serotonin, 5-HT3; Serotonin; Protein Transport; Protein Binding; Ligand-Gated Ion Channels; Receptors, Purinergic P2X4
PubMed: 37156336
DOI: 10.1016/j.neuropharm.2023.109574 -
Purinergic Signalling Sep 2023Extracellular adenosine 5'-triphosphate (ATP) acts as an autocrine and paracrine agent, the actions of which on affected cells are mediated by P2 receptors (P2R), which...
Extracellular adenosine 5'-triphosphate (ATP) acts as an autocrine and paracrine agent, the actions of which on affected cells are mediated by P2 receptors (P2R), which include trans cell-membrane cationic channels (P2XRs), and G protein coupled receptors (P2YRs). The mammalian P2X receptors form homotrimeric or heterotrimeric cationic channels, each of which contains three ATP-binding sites. There are seven homotrimeric P2X receptors (P2X1-7) and three heteromeric (P2X2/P2X3, P2X4/P2X6, P2X1/P2X5). In the lungs and airways, ATP activates P2X3 and P2X2/3 receptors (P2X3R, P2X2/3R, respectively) localized on vagal sensory nerve terminals resulting in bronchoconstriction, and cough, and probably also localized release of pro-inflammatory neuropeptides via the axon reflex. Currently, several P2X3R and P2X2/3R antagonists are being developed as drug-candidates for the treatment of chronic cough. This report presents the receptor affinity data of a novel water-soluble small molecule, DT-0111, that acts as a selective P2X3R antagonist.
Topics: Animals; Cough; Receptors, Purinergic P2X3; Purinergic P2X Receptor Antagonists; Adenosine Triphosphate; Lung; Receptors, Purinergic P2X2; Mammals
PubMed: 36944825
DOI: 10.1007/s11302-023-09930-5 -
International Journal of Molecular... Jul 2023Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by impaired episodic memory and two pathological lesions: amyloid plaques and... (Review)
Review
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by impaired episodic memory and two pathological lesions: amyloid plaques and neurofibrillary tangles. In AD, damaged neurons and the accumulation of amyloid β (Aβ) peptides cause a significant release of high amounts of extracellular ATP, which acts as a danger signal. The purinergic receptor P2X7 is the main sensor of high concentrations of ATP, and P2X7 has been shown to be upregulated in the brains of AD patients, contributing to the disease's pathological processes. Further, there are many polymorphisms of the gene that impact the risk of developing AD. P2X7 can directly modulate Aβ plaques and Tau protein lesions as well as the inflammatory response by regulating NLRP3 inflammasome and the expression of several chemokines. The significant role of microglial P2X7 in AD has been well established, although other cell types may also be important in P2X7-mediated mechanisms. In this review, we will discuss the different P2X7-dependent pathways involved in the development of AD.
Topics: Humans; Adenosine Triphosphate; Alzheimer Disease; Amyloid beta-Peptides; Microglia; Neurodegenerative Diseases; Receptors, Purinergic P2X7
PubMed: 37511507
DOI: 10.3390/ijms241411747 -
Purinergic Signalling Feb 2024A variety of observational studies have demonstrated that coffee, likely acting through caffeine, improves health outcomes in patients with chronic liver disease. The... (Review)
Review
A variety of observational studies have demonstrated that coffee, likely acting through caffeine, improves health outcomes in patients with chronic liver disease. The primary pharmacologic role of caffeine is to act as an inhibitor of adenosine receptors. Because key liver cells express adenosine receptors linked to liver injury, regeneration, and fibrosis, it is plausible that the biological effects of coffee are explained by effects of caffeine on adenosinergic signaling in the liver. This review is designed to help the reader make sense of that hypothesis, highlighting key observations in the literature that support or dispute it.
Topics: Humans; Coffee; Caffeine; Liver Cirrhosis; Adenosine; Liver; Receptors, Purinergic P1
PubMed: 37755557
DOI: 10.1007/s11302-023-09968-5