Purinergic Signalling最新文献

{"title":"Purinergic regulation of pulmonary vascular tone.","authors":"Marco Alveal, Andrea Méndez, Aline García, Mauricio Henríquez","doi":"10.1007/s11302-024-10010-5","DOIUrl":"10.1007/s11302-024-10010-5","url":null,"abstract":"<p><p>Purinergic signaling is a crucial determinant in the regulation of pulmonary vascular physiology and presents a promising avenue for addressing lung diseases. This intricate signaling system encompasses two primary receptor classes: P1 and P2 receptors. P1 receptors selectively bind adenosine, while P2 receptors exhibit an affinity for ATP, ADP, UTP, and UDP. Functionally, P1 receptors are associated with vasodilation, while P2 receptors mediate vasoconstriction, particularly in basally relaxed vessels, through modulation of intracellular Ca²⁺ levels. The P2X subtype receptors facilitate extracellular Ca²⁺ influx, while the P2Y subtype receptors are linked to endoplasmic reticulum Ca²⁺ release. Notably, the primary receptor responsible for ATP-induced vasoconstriction is P2X1, with α,β-meATP and UDP being identified as potent vasoconstrictor agonists. Interestingly, ATP has been shown to induce endothelium-dependent vasodilation in pre-constricted vessels, associated with nitric oxide (NO) release. In the context of P1 receptors, adenosine stimulation of pulmonary vessels has been unequivocally demonstrated to induce vasodilation, with a clear dependency on the A_2B receptor, as evidenced in studies involving guinea pigs and rats. Importantly, evidence strongly suggests that this vasodilation occurs independently of endothelium-mediated mechanisms. Furthermore, studies have revealed variations in the expression of purinergic receptors across different vessel sizes, with reports indicating notably higher expression of P2Y₁, P2Y₂, and P2Y₄ receptors in small pulmonary arteries. While the existing evidence in this area is still emerging, it underscores the urgent need for a comprehensive examination of the specific characteristics of purinergic signaling in the regulation of pulmonary vascular tone, particularly focusing on the disparities observed across different intrapulmonary vessel sizes. Consequently, this review aims to meticulously explore the current evidence regarding the role of purinergic signaling in pulmonary vascular tone regulation, with a specific emphasis on the variations observed in intrapulmonary vessel sizes. This endeavor is critical, as purinergic signaling holds substantial promise in the modulation of vascular tone and in the proactive prevention and treatment of pulmonary vascular diseases.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":"595-606"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140857415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metastasis and angiogenesis in cervical cancer: key aspects of purinergic signaling in platelets and possible therapeutic targets.","authors":"Paula C L Faria, Rackel S Resende, Andréia M Cardoso","doi":"10.1007/s11302-024-10020-3","DOIUrl":"10.1007/s11302-024-10020-3","url":null,"abstract":"<p><p>Cervical cancer ranks as the fourth most common and fatal cancer among women worldwide. Studies have demonstrated a strong association between purinergic platelet signaling and tumor progression in this type of cancer. The literature shows that neoplastic cells, when in the bloodstream, secrete adenosine triphosphate (ATP) and adenosine nucleotide diphosphate (ADP) that act on their corresponding platelet P2Y and P2X receptors. The interaction of these nucleotides with their receptors results in platelet activation and degranulation, ensuing several consequences, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor, matrix metalloproteinases, ADP, and ATP. These molecules play essential roles in angiogenesis and tumor metastasis in cervical cancer. Several purinergic receptors are found in endothelial cells. Their activation, especially P2Y2, by the nucleotides released by platelets can induce relaxation of the endothelial barrier and consequent extravasation of tumor cells, promoting the development of metastases. Cancer cells that enter the bloodstream during the metastatic process are also subject to high shear stress and immune surveillance. In this context, activated platelets bind to circulating tumor cells and protect them against shear stress and the host's immune system, especially against natural killer cells, facilitating their spread throughout the body. Furthermore, activation of the P2Y12 receptor present on the platelet surface promotes the release of VEGF, the main inducer of angiogenesis in cervical cancer, in addition to increasing the concentration of several other pro-angiogenic molecules. Therefore, this review will address the role of platelet purinergic signaling in tumor progression of cervical cancer and propose possible therapeutic targets.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":"607-616"},"PeriodicalIF":4.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140945828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological differences between human and mouse P2X4 receptor explored using old and new tools.","authors":"Anna Fortuny-Gomez, Samuel J Fountain","doi":"10.1007/s11302-024-10018-x","DOIUrl":"10.1007/s11302-024-10018-x","url":null,"abstract":"<p><p>There is growing interest in the P2X4 receptor as a therapeutic target for several cardiovascular, inflammatory and neurological conditions. Key to exploring the physiological and pathophysiological roles of P2X4 is access to selective compounds to probe function in cells, tissues and animal models. There has been a recent growth in selective antagonists for P2X4, though agonist selectivity is less well studied. As there are some known pharmacological differences between P2X receptors from different species, it is important to understand these differences when designing a pharmacological strategy to probe P2X4 function in human tissue and mouse models. Here, we provide a systematic comparison of agonist and antagonist pharmacology in 1321N1 cells expressing either human or mouse P2X4 orthologues. We identify a rank order of agonist potency of ATP > 2-MeSATP > αβmeATP = BzATP > CTP = γ-[(propargyl)-imido]-ATP for human P2X4 and ATP > 2-MeSATP = CTP > ATPγS = γ-[(propargyl)-imido]-ATP = BzATP for mouse. Human P2X4 is not activated by ATPγS but can be activated by αβmeATP. We identify a rank order of antagonist potency of BAY-1797 = PSB-12062 = BX-430 > 5-BDBD > TNP-ATP = PPADS for human P2X4 and BAY-1797 > PSB-12062 = PPADS > TNP-ATP for mouse. Mouse P2X4 is not antagonised by 5-BDBD or BX-430. The study reveals key pharmacological differences between human and mouse P2X4, highlighting caution when selecting tools for comparative studies between human and mouse and ascribing cellular responses of some commonly used agonists to P2X4.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":"659-667"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141065551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preparation and preliminary evaluation of a tritium-labeled allosteric P2X4 receptor antagonist.","authors":"Jessica Nagel, Olli Törmäkangas, Katja Kuokkanen, Ali El-Tayeb, Josef Messinger, Aliaa Abdelrahman, Christiane Bous, Anke C Schiedel, Christa E Müller","doi":"10.1007/s11302-024-10005-2","DOIUrl":"10.1007/s11302-024-10005-2","url":null,"abstract":"<p><p>P2X4 receptors are ATP-gated cation channels that were proposed as novel drug targets due to their role in inflammation and neuropathic pain. Only few potent and selective P2X4 receptor antagonists have been described to date. Labeled tool compounds suitable for P2X4 receptor binding studies are lacking. Here, we present a novel allosteric P2X4 receptor antagonist possessing high potency in the low nanomolar range. We describe its tritium-labeling resulting in the P2X4-selective radiotracer [³H]PSB-OR-2020 with high specific activity (45 Ci/mmol; 1.67 TBq/mmol). A radioligand binding assay was developed using human embryonic kidney (HEK293) cell membranes recombinantly expressing the human P2X4 receptor. Competition binding studies with structurally diverse P2X4 receptor antagonists revealed different allosteric binding sites indicating that the new class of P2X4 receptor antagonists, to which PSB-OR-2020 belongs, interacts with an unprecedented allosteric site. [³H]PSB-OR-2020 may become a useful tool for research on P2X4 receptors and for promoting drug development.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":"645-656"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141097011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unexpected role of microglia and P2Y₁₂ in the induction of and emergence from anesthesia.","authors":"Bijay Parajuli, Schuichi Koizumi","doi":"10.1007/s11302-024-10014-1","DOIUrl":"10.1007/s11302-024-10014-1","url":null,"abstract":"","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":"573-575"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140896098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine learning-aided search for ligands of P2Y₆ and other P2Y receptors.","authors":"Ana C Puhl, Sarah A Lewicki, Zhan-Guo Gao, Asmita Pramanik, Vadim Makarov, Sean Ekins, Kenneth A Jacobson","doi":"10.1007/s11302-024-10003-4","DOIUrl":"10.1007/s11302-024-10003-4","url":null,"abstract":"<p><p>The P2Y₆ receptor, activated by uridine diphosphate (UDP), is a target for antagonists in inflammatory, neurodegenerative, and metabolic disorders, yet few potent and selective antagonists are known to date. This prompted us to use machine learning as a novel approach to aid ligand discovery, with pharmacological evaluation at three P2YR subtypes: initially P2Y₆ and subsequently P2Y₁ and P2Y₁₄. Relying on extensive published data for P2Y₆R agonists, we generated and validated an array of classification machine learning model using the algorithms deep learning (DL), adaboost classifier (ada), Bernoulli NB (bnb), k-nearest neighbors (kNN) classifier, logistic regression (lreg), random forest classifier (rf), support vector classification (SVC), and XGBoost (XGB) classifier models, and the common consensus was applied to molecular selection of 21 diverse structures. Compounds were screened using human P2Y₆R-induced functional calcium transients in transfected 1321N1 astrocytoma cells and fluorescent binding inhibition at closely related hP2Y₁₄R expressed in CHO cells. The hit compound ABBV-744, an experimental anticancer drug with a 6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine scaffold, had multifaceted interactions with the P2YR family: hP2Y₆R inhibition in a non-surmountable fashion, suggesting that noncompetitive antagonism, and hP2Y₁R enhancement, but not hP2Y₁₄R binding inhibition. Other machine learning-selected compounds were either weak (experimental anti-asthmatic drug AZD5423 with a phenyl-1H-indazole scaffold) or inactive in inhibiting the hP2Y₆R. Experimental drugs TAK-593 and GSK1070916 (100 µM) inhibited P2Y₁₄R fluorescent binding by 50% and 38%, respectively, and all other compounds by < 20%. Thus, machine learning has led the way toward revealing previously unknown modulators of several P2YR subtypes that have varied effects.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":"617-627"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140288821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular mechanisms of extracellular-ATP-mediated colorectal cancer progression: Implication of purinergic receptors-mediated nucleocytoplasmic shuttling of HuR.","authors":"Abdel-Aziz S Shatat, Elsayed M Mahgoup, Mohammed H Rashed, Ibrahim G Saleh, El-Sayed Akool","doi":"10.1007/s11302-024-10021-2","DOIUrl":"10.1007/s11302-024-10021-2","url":null,"abstract":"<p><p>One of the leading causes of cancer-related deaths worldwide is colorectal cancer (CRC). Extracellular ATP (e-ATP) and purinergic receptors (P2R) play a central role in CRC proliferation and progression. Human antigen R (HuR) is becoming more and more understood to be essential for the expression of genes linked to cancer. The current study demonstrates that ATP can mediate CRC (Caco-2 cells) progression via induction of HuR nucleocytoplasmic shuttling and subsequent expression of cancer-related genes, a consequence mostly mediated via the P2R receptor. It was also noted that suppression of HuR activity by using dihydrotanshinone I (DHTS) prevents cancer-related gene expression and subsequent CRC (Caco-2 cells) progression induced by ATP. The expression of cyclin A2/cyclin-dependent kinase 2 (CDK2), Bcl-2, ProT-α, hypoxia-inducible factor1-α (HIF1-α), vascular endothelial growth factor A (VEGF-A), transforming growth factor-β (TGF-β) and matrix metallopeptidase 9 (MMP-9) induced by ATP were highly reduced in the presence of either PPADS (non-selective P2R antagonist) or DHTS. In addition, e-ATP-induced Caco-2 cell proliferation as well as cell survival were highly reduced in the presence of either PPADS or DHTS or selective CDK-2 inhibitor (Roscovitine) or selective Bcl-2 inhibitor (ABT-263). Furthermore, it was found that MMP-9 is critical for Caco-2 cells migration induced by e-ATP as demonstrated by a clear reduction in cells migration in the presence of a selective MMP-9 inhibitor (Marimastat). Collectively, these data demonstrate that ATP through P2R activation can induce HuR nucleocytoplasmic shuttling that could be translated into an increase in cancer-related genes expression and subsequent, cell proliferation and progression.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":"669-680"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141155008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of ecto-5'-nucleotidase in bladder function activity and smooth muscle contractility.","authors":"Basu Chakrabarty, Bahareh Vahabi","doi":"10.1007/s11302-024-10015-0","DOIUrl":"10.1007/s11302-024-10015-0","url":null,"abstract":"","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":"577-579"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140892455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Purinergic P2Y₁ and P2Y₁₂ receptors control enteric nervous system activity through neuro-glia-macrophage crosstalk.","authors":"Blake J Hendler, Jonathon L McClain, Aurora Zilli, Luisa Seguella, Brian D Gulbransen","doi":"10.1007/s11302-024-10060-9","DOIUrl":"https://doi.org/10.1007/s11302-024-10060-9","url":null,"abstract":"<p><p>Purines are important mediators of intercellular communication in the enteric nervous system (ENS) that participate in physiological gut functions and disease. Purinergic transmission is prominent in mechanisms of crosstalk between enteric neurons and glia where enteric glia exhibit high responsiveness to adenosine diphosphate (ADP) through P2Y₁ receptors and neurons to adenosine triphosphate (ATP) through P2X₃ receptors. Despite functional data suggesting that enteric glia are the primary site of P2Y₁ expression in the ENS, gene sequencing suggests that P2Y₁ expression is more enriched in neurons than glia. The reason for the mismatch between genomic and functional data is unclear but could involve co-expression of inhibitory P2Y₁₂ receptors in neurons. We addressed this issue by studying the expression and function of P2Y₁ and P2Y₁₂ receptors in the mouse ENS using live immunolabeling and calcium imaging techniques. The data show that ADP drives activity among enteric glia and neurons in the myenteric plexus. Interestingly, inhibiting P2Y₁₂ activity increased neuron responses to ADP and overall spontaneous activity among enteric neurons and glia while decreasing the magnitude of glial responses to ADP. Investigating the location of the receptors involved revealed P2Y₁ receptor expression by both neurons and glia, while P2Y₁₂ receptor expression was minimal in the ENS. Instead, P2Y₁₂ expression was enriched in the surrounding muscularis macrophages. Macrophages positive for P2Y₁₂ overlapped with CD163 positive subsets that have known inhibitory influences over myenteric neurocircuits. Together, these data suggest that macrophage P2Y₁₂ pathways act to constrain activity in the ENS, which could have implications in mechanisms that contribute to enteric hyperexcitability following disease.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of the P2X7 receptor in inactivated SARS-CoV-2-induced lung injury.","authors":"N C Carvalho-Barbosa, Fabiana Cristina-Rodrigues, Jairo R Temerozo, Thiago M L Souza, Andre L Gouvêa, Claudio A Canetti, Eleonora Kurtenbach, Dumith Chequer Bou-Habib, Claudia F Benjamim, Christina M Takiya, Luiz E B Savio, Robson Coutinho-Silva","doi":"10.1007/s11302-024-10062-7","DOIUrl":"https://doi.org/10.1007/s11302-024-10062-7","url":null,"abstract":"<p><p>Purinergic signaling plays a role in the pathophysiology of different viral infections. Recently, we showed that COVID-19 increases extracellular ATP levels, which may amplify the pro-inflammatory signals in the disease. The P2X7 receptor can be a protagonist in the pro-inflammatory responses. Herein, we investigated the role of the P2X7 receptor in the lung immune response triggered by inoculation of inactivated SARS-CoV-2 (iSARS-CoV-2) in K18-Human ACE2 transgenic mice. Pharmacological inhibition of the P2X7 receptor was performed with intraperitoneal administration of 50 mg/kg of Brilliant Blue G (BBG) one day before viral inoculation. Animals were divided into four groups: a control group (MOCK), a group inoculated with the inactivated virus iSARS-CoV-2, a BBG-treated control group (MOCK + BBG), and a BBG-treated inoculated group (iSARS-CoV-2 + BBG). Virus inoculation was intratracheal with 50 µl of mock or 2 × 10⁶ Plaque Forming Units (PFU) of iSARS-CoV-2. After three days, blood and lungs were collected. We found a significant increase in ATP and LDH in serum and mRNA levels of P2X7 and P2Y₁₂ receptors, CD39, IL-1β, and TNF-α in the lung of the iSARS-CoV-2 group when compared with the control group. BBG treatment attenuated these increases. Lung histological analyses showed severe lung damage in the iSARS-CoV-2 group, which was reduced by the BBG treatment. Immunohistochemical staining confirmed the increased presence of P2X7, P2Y₁₂, and CD39 proteins in the iSARS-CoV-2 vs. the MOCK group. Thus, P2X7 receptor inhibition decreases iSARS-CoV-2-induced lung inflammation, indicating that this receptor might contribute to SARS-CoV-2 pathology.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}