Purinergic Signalling最新文献

{"title":"A_2B adenosine receptor-triggered intracellular calcium mobilization: Cell type-dependent involvement of G_i, G_q, G_s proteins and protein kinase C.","authors":"Zhan-Guo Gao, Ray R Gao, Clayton K Meyer, Kenneth A Jacobson","doi":"10.1007/s11302-025-10070-1","DOIUrl":"10.1007/s11302-025-10070-1","url":null,"abstract":"<p><p>Activation of PLCβ enzymes by G_iβγ and G_αq/11 proteins is a common mechanism to trigger cytosolic Ca²⁺ increase. We and others reported that G_αq/11 inhibitor FR900359 (FR) can inhibit both G_αq- and, surprisingly, G_iβγ-mediated intracellular Ca²⁺ mobilization. Thus, the G_αi-G_βγ-PLCβ-Ca²⁺ signaling axis depends entirely on the presence of active G_αq, which reasonably explained FR-inhibited G_iβγ-induced Ca²⁺ release. However, the conclusion that G_iβγ signaling is controlled by G_αq derives mostly from HEK293 cells. Here we show that indeed in HEK293 cells both G_αq/11 siRNA and G_αq/11 inhibitors diminished Ca²⁺ increase triggered by native G_q-coupled P2Y₁ receptors, or by transfected G_i-coupled A₁- or G_s-coupled A_2B adenosine receptors (ARs). However, in T24 bladder cancer cells, G_i inhibitor PTX, but not G_αq/11 inhibitors, FR, YM254890 (YM) or G_q/11 siRNA, inhibited Ca²⁺ increase triggered by native A_2BAR activation. Simultaneous inactivation of G_i and G_s further suppressed A_2BAR-triggered Ca²⁺ increase in T24 cells. The G_αq/11 inhibitor YM fully and partially inhibited endogenous P2Y₁- and β₂-adrenergic receptor-induced Ca²⁺ increase in T24 cells, respectively. PKC activator PMA partially diminished A_2BAR-triggered but completely diminished β₂-adrenergic receptor-triggered Ca²⁺ increase in T24 cells. Neither β-arrestin1 nor β-arrestin2 siRNA affected A_2BAR-mediated Ca²⁺ increase. Unlike in T24 cells, YM inhibited native A_2BAR-triggered calcium mobilization in MDA-MB-231 breast cancer cells. Thus, G_αq/11 is vital for Ca²⁺ increase in some cell types, but G_iβγ-mediated Ca²⁺ signaling can be Gα_q/11-dependent or independent based on cell type and receptor activated. Besides G proteins, PKC also modulates cytosolic Ca²⁺ increase depending on cell type and receptor.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399825","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":"Adventures in translation.","authors":"Bruce Cronstein, Sid Angle","doi":"10.1007/s11302-025-10069-8","DOIUrl":"https://doi.org/10.1007/s11302-025-10069-8","url":null,"abstract":"","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029422","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":"Purinergic signaling in health: special issue of purines 2022 in Brazil.","authors":"Henning Ulrich, Carla I Tasca, Claudiana Lameu","doi":"10.1007/s11302-025-10067-w","DOIUrl":"https://doi.org/10.1007/s11302-025-10067-w","url":null,"abstract":"","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143010624","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":"Extracellular ATP regulates phagocytic activity, mitochondrial respiration, and cytokine secretion of human astrocytic cells.","authors":"Sijie Shirley Yang, Noah A H Brooks, Dylan E Da Silva, Julien Gibon, Hashim Islam, Andis Klegeris","doi":"10.1007/s11302-025-10066-x","DOIUrl":"https://doi.org/10.1007/s11302-025-10066-x","url":null,"abstract":"<p><p>The two main glial cell types of the central nervous system (CNS), astrocytes and microglia, are responsible for neuroimmune homeostasis. Recent evidence indicates astrocytes can participate in removal of pathological structures by becoming phagocytic under conditions of neurodegenerative disease when microglia, the professional phagocytes, are impaired. We hypothesized that adenosine triphosphate (ATP), which acts as damage-associated molecular pattern (DAMP), when released at high concentrations into extracellular space, upregulates phagocytic activity of human astrocytes. This study is the first to measure changes in phagocytic activity and mitochondrial respiration of human astrocytic cells in response to extracellular ATP. We demonstrate that ATP-induced phagocytic activity of U118 MG astrocytic cells is accompanied by upregulated mitochondrial oxidative phosphorylation, which likely supports this energy-dependent process. Application of a selective antagonist A438079 provides evidence identifying astrocytic purinergic P2X7 receptor (P2X7R) as the potential regulator of their phagocytic function. We also report a rapid ATP-induced increase in intracellular calcium ([Ca²⁺]_i), which could serve as regulator of both the phagocytic activity and mitochondrial metabolism, but this hypothesis will need to be tested in future studies. Since ATP upregulates interleukin (IL)-8 secretion by astrocytes but has no effect on their cytotoxicity towards neuronal cells, we conclude that extracellular ATP affects only specific functions of astrocytes. The selectivity of P2X7R-dependent regulation of astrocyte functions by extracellular ATP could allow targeting this receptor-ligand interaction to upregulate their phagocytic function. This could have beneficial outcomes in neurodegenerative disorders, such as Alzheimer's disease, that are characterized by reactive astrocytes and defective phagocytic processes.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143010617","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":"P2Y₁R-IGFBP2 signaling: new contributor to astrocyte-neuron communication.","authors":"Dan Huang, Yong Tang","doi":"10.1007/s11302-025-10068-9","DOIUrl":"https://doi.org/10.1007/s11302-025-10068-9","url":null,"abstract":"<p><p>In a recent article published in Nature Communications (Shigetomi et al Nat Commun 15(1):6525, 2024), Shigetomi et al. identified that upregulated astrocytic purinergic P2Y₁ receptors (P2Y₁R), acting via the downstream molecule, insulin-like growth factor binding protein 2 (IGFBP2), play a crucial role in neuronal hyperexcitability. In epilepsy and stroke models, P2Y₁R-IGFBP2 signaling was found to mediate astrocyte-driven neuronal hyperexcitability and so is a new contributor to astrocyte-neuron communication. Thus, IGFBP2 could be an alternative target for treating the effects of upregulated P2Y₁R activity in reactive astrocytes in neurological diseases.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143010621","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":"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}