Interaction between purinergic signalling and purinergic modulators with skin wound repair effectors: a systematic review of preclinical in vivo models - Silvânia Mól Pelinsari; Reggiani Vilela Goncalves; Patricia da Silva Mattosinhos; Mariáurea Matias Sarandy; Emerson Ferreira Vilela; Rômulo Dias Novaes (Purinergic Signalling, 2026)
Purinergic signalling plays a central regulatory role on cell proliferation, migration, differentiation, survival, and inflammation. However, the impact of purinergic modulators-based therapies on tissue repair is still overlooked. By using a systematic review framework, we investigated the therapeutic relevance of purinergic agonists and antagonists in animal models of skin wound healing. Following PRISMA guidelines, PubMed/Medline, Scopus, Web of Science, Embase, and CINAHL databases were searched, identifying 12 in vivo preclinical studies. Risk of bias was assessed using the SYRCLE tool. Topical or oral administration of CGS-21680 (4-[{ N -ethyl-5 ’ -carbamoyladenos-2-yl}aminoethyl] phenylpropionic acid), UTP (Uridine-5'-triphosphate), NECA (5'-N-ethylcarboxamidoadenosine), ATP (adenosine triphosphate), PDRN (polydeoxyribonucleotide), ADP (Adenosine-5'-diphosphate) and TMPS (Thymidine 5'-O-monophosphorothioate) agonists stimulated wound contraction, fibroblast and keratinocyte proliferation, angiogenesis, and collagen biosynthesis. These effects were associated with activation of Nrf2 (Nuclear factor erythroid 2–related factor 2), MAPK (Mitogen-Activated Protein Kinase), and ERK/CREB pathways, inflammation and oxidative/nitrosative stress down-regulation, and increased anti-inflammatory/regulatory cytokines (IL-10, IL-13, TGF-β) and growth factors (FGF, EGF). Conversely, the purinergic antagonists DMPX (3,7-dimethyl-1-propargylxanthine), CSC (8-(3-chlorostyryl) caffeine), SUR (Suramin), ENP (enprofylline), caffeine, CLOP (clopidogrel), MRS 2179 (2′-deoxy-N6-methyladenosine-3′,5′-bisphosphate), and MRS 2395 (2-Chloro-3′,5′-O-(benzoyl-β,γ-methylene) adenosine 5′-triphosphate), as well as genetic knockout for purinergic receptors delayed wound closure by inhibiting these pathways, impairing angiogenesis, collagenogenesis, and aggravating inflammation and oxidative damage. Purinergic agonists were associated with improved wound healing through inflammatory and oxidative modulation, enhanced angiogenesis, increased cell proliferation, and accelerated wound closure, whereas antagonists or genetic deficiency of purinergic receptors impaired tissue repair. This review was registered in the PROSPERO database (CRD420251010254). Graphical abstract Overview of the effects of purinergic signalling modulation on cutaneous wound healing in murine models. Purinergic receptor activation by agonists accelerates wound closure, enhances cell proliferation and angiogenesis, and attenuates oxidative stress and pro-inflammatory cytokine production through activation of the PKA/ERK/CREB pathway. Conversely, receptor inhibition by antagonists or genetic deletion (KO) disrupts downstream signalling, resulting in delayed wound healing and increased inflammatory and oxidative damage.

Effects on mouse melanoma and immune cells of P2X7 receptor positive allosterism by clemastine - Maria Luiza Thorstenberg; Simonetta Falzoni; Rocio Edith Garcia-Jacobo; Leticia Scussel Bergamin; Mario Tarantini; Giulia Conversano; Anna Pegoraro; Francesco Di Virgilio; Elena Adinolfi; Anna Lisa Giuliani (Purinergic Signalling, 2026)
Clemastine (CLE), an H1R antagonist widely used for the treatment of allergic rhinitis, has recently been investigated for its positive modulatory effects on P2X7, a receptor for extracellular ATP (eATP) involved in the regulation of inflammation, immune responses, and the composition of the tumor microenvironment (TME). Here, we further examined the effects of CLE on P2X7-mediated responses to clarify the pharmacological significance of P2X7 potentiation. First, in murine and human cells expressing (B16F10 WT and HEK293-hP2X7) or lacking (B16F10 P2X7 −/− and HEK293 WT) the P2X7 receptor, we measured intracellular Ca 2+ influx, ethidium bromide (EB) and daunorubicin (DN) uptake, mitochondrial morphology, and LDH and ATP release following P2X7 agonism or antagonism in the presence of CLE. We found that CLE increased Bz-ATP-induced P2X7-mediated channel opening, pore formation, mitochondrial remodeling, eATP release, and cell death, effects absent in P2X7-null cells and abolished by P2X7 antagonists. As a readout of activation of NLRP3 inflammasome, a known downstream effector of the P2X7 receptor, we also assessed the effect of CLE on IL-1β release from peritoneal macrophages from wild-type (WT) or P2X7 knockout (KO) mice, LPS-primed and treated with ATP and/or CLE. We found that the combined treatment significantly increased IL-1β release from P2X7-WT macrophages compared to the two stimuli administered separately. On the whole, our results demonstrate that CLE can effectively positively modulate P2X7 function, suggesting new opportunities for its therapeutic exploitation.

Differential expression, activity, and fibroblast growth factor 2-mediated modulation of purine-metabolizing enzymes in cultured cortical astrocytes and microglia - Ryota Eguchi; Ken-ichi Otsuguro (Purinergic Signalling, 2026)

The P2X7 receptor: insights from the murine monoclonal antibody clone L4 - Ronald Sluyter; Amal Elhage; Rachael Bartlett; Debbie Watson; Leanne Stokes; Kristen K. Skarratt; Stephen J. Fuller; Ben J. Gu (Purinergic Signalling, 2026)
The P2X7 receptor (or P2X7) is an ATP-gated ion channel with important roles in the immune and other body systems. Much has been garnered about P2X7 using the first published anti-human P2X7 monoclonal antibody (mAb) (clone L4). This mAb can be used to impair P2X7 channel and pore activity and events downstream of P2X7 activation in vitro and in vivo. Immunolabelling with this mAb has been used in flow and mass cytometry, confocal microscopy and immunohistochemistry to help establish the presence of P2X7 on human leukocytes and other primary cell types, as well as various malignant cell lines. This mAb has been applied to immunoprecipitate P2X7 to identify co-associated molecules to help uncover novel roles of the receptor such as phagocytosis. Recently, this mAb has been shown to mediate complement-dependent cytotoxicity, offering a new avenue of limiting P2X7-mediated processes by depleting P2X7 + cells. Finally, this mAb has been used to identify and characterise polymorphic and other variants of P2X7. This article will discuss the origins and various applications of the anti-P2X7 mAb (clone L4). As an early user of this mAb and pioneer of other purinergic technologies, this article is a tribute to the late Francesco Di Virgilio.

Is adenosine signalling entering the precision medicine era? From receptor pharmacology to patient stratification - Luca Antonioli; György Haskó (Purinergic Signalling, 2026)

Inflammation, oxidative stress and purinergic signaling in pituitary neuroendocrine tumors (PitNETs) - Yenidis Teilor Scheibel; Symon Martins; André Paulo Turcatel; Francini Franscescon; Débora Tavares de Resende e Silva (Purinergic Signalling, 2026)
Pituitary neuroendocrine tumors (PitNETs) constitute a heterogeneous group of intracranial neoplasms with variable biological behavior, whose aggressiveness cannot be explained solely by the intrinsic characteristics of tumor cells. Growing evidence demonstrates that chronic inflammation of the tumor microenvironment (TME) plays a central role in the progression, invasiveness, therapeutic resistance, and recurrence of these tumors. In this context, the purinergic system emerges as a fundamental regulatory axis of the local inflammatory response, integrating signals derived from cellular stress, hypoxia, and metabolic reprogramming. The extracellular release of ATP under conditions of oxidative stress, tissue damage, and cell death serves as a pro-inflammatory signal by activating P2 purinergic receptors. On the other hand, its conversion to adenosine by the ectonucleotidases CD39 and CD73 promotes an immunosuppressive environment, mainly through P1 receptors, such as A2A and A2B. This dynamic balance modulates the infiltration and polarization of immune cells, the production of inflammatory cytokines, including IL-6, IL-8, and TNF-α, the activation of transcriptional pathways such as NF-κB, STAT3, and HIF-1α, and extracellular matrix remodeling and angiogenesis. This study aims to review the role of inflammation in the tumor microenvironment of PitNETs, with emphasis on purinergic signaling as an integrating link between oxidative stress, immune dysfunction, and metabolic reprogramming. Although not abundantly explored, the purinergic pathway in PitNETs shows promising potential: it interconnects different elements of the TME, contributes to tumor mechanisms, and is a potential target for immunomodulatory and anti-inflammatory therapies in pituitary tumors.

Responsiveness to adenosine diphosphate on carotid arterial and platelet functions in type 2 diabetic Otsuka Long-Evans Tokushima Fatty rats - Hideaki Tagashira; Kumiko Taguchi; Takayuki Nagano; Tsuneo Kobayashi; Hiroaki Kimura; Naoko Tanaka-Totoribe; Takayuki Matsumoto (Purinergic Signalling, 2026)

The effect of P2RX7 functional SNPs on osteoblast cell phenotype, function and signalling- roles in bone homeostasis and osteogenesis - Luke Tattersall; Qiguang Wang; Anna Lisa Giuliani; Elena Adinolfi; Alison Gartland (Purinergic Signalling, 2026)
Bone cells are known to express multiple purinergic receptors. These are involved in various aspects of bone physiology depending on the cell type and receptor involved, both in normal and disease states, with extracellular ATP being particularly abundant in the bone microenvironment. The P2X7R subtype has been the subject of in-depth research in bone homeostasis. Different splice isoforms and single nucleotide polymorphisms (SNPs) have been discovered in the P2RX7 gene, these have functional implications on the receptor, conferring both gain of function (GOF) and loss of function (LOF), with consequences for bone phenotype, turnover and mass. We examined the full length P2RX7A , truncated P2RX7B, their co-expression and different receptor SNPs. The SNPs included the c.489C > T variant (p.His155Tyr) GOF, c.946G > A (p.Arg307Gln) LOF and c.1513A > C (p.Glu496Ala) LOF. The effect of these isoforms and SNPs on the normal cellular behaviour of the TE85 osteoblastic cell line were measured for intracellular calcium uptake, pore formation, cell proliferation, Alkaline phosphatase (ALP) activity, mineralisation, and changes in osteogenic gene expression. The results demonstrate that transfection of P2RX7 isoforms and SNP variants influenced several important bone processes. Compared to TE85 cells all isoform variants had an increased calcium response with only the co-transfected P2RX7AB having pore formation. This variant also had the highest mineralisation and ALP activity but was the least proliferative. Of the co-transfected SNP variants only the TE85 + P2RX7B + 155Y GOF cell line had both pore formation and an increased calcium response. Mineralisation was lower in all SNP cell lines as was ALP activity, however, proliferation was increased. Mechanistically, gene expression arrays showed that Nuclear Factor of Activated T-cells 1 ( NFATc1 ) increased in the highly proliferative cell variants. Osteogenic genes such as Bone morphogenetic protein 2 ( BMP2) , ALP and collagen type I alpha 1 chain ( COL1A1 ) were increased in the cell variants that had high mineralisation and ALP activity, and were decreased in the highly proliferative variants, demonstrating multiple bone phenotypes depending on GOF or LOF. In conclusion, this study extends our knowledge into the role of the P2X7R in maintaining bone homeostasis and provides assessment of P2RX7 polymorphisms in osteoblasts. In future this could help to identify associations between specific variants and increased/reduced bone mineral density or accelerated bone loss/fracture risk in a number of bone related conditions.

Selective P2X3 versus dual P2X2/3 receptor antagonists in refractory chronic cough: a systematic review and dose–response meta-analysis of randomized controlled trials - Jeevarathinam Thirumalai; Indra Sivakumar; Saravanan Sekaran (Purinergic Signalling, 2026)

A tale of two ATPs: biased activation of the P2X3 receptor - Paul-Pierre Boutet (Purinergic Signalling, 2026)

Correction to: The analgesic effect of electroacupuncture in alleviating paclitaxel-induced peripheral neuropathic pain and its possible mechanism relates to TLR4/P2X7-NLRP3 signaling pathway - Yuan-xi Zhou; Man-ni Wang; Juan-juan Xin; Jing-wei Tan; Xiao Sang; Yu-xue Zhao (Purinergic Signalling, 2026)

Adenosine A2A receptor signaling in neuroinflammation, glial modulation, and mechanisms associated with chronic pain - Clara Andressa Barros; Jéssica Gonçalves Rangel; Bruno de Oliveira Cruz; Leonardo Pereira De Araújo; Giovane Galdino (Purinergic Signalling, 2026)
Chronic pain is increasingly recognized as a complex and multidimensional condition that extends beyond peripheral nociceptive input, encompassing maladaptive central mechanisms such as persistent neuroinflammation, glial dysfunction, aberrant synaptic plasticity, and disturbances in affective–motivational circuits. Adenosine, an endogenous purine nucleoside, plays a pivotal role in central nervous system homeostasis through activation of four G protein–coupled receptors (A1, A2A, A2B, and A3). Among these, the adenosine A2A receptor (A2AR) has emerged as an important modulator of neuroimmune signaling, astrocyte–neuron communication, synaptic excitability, and behavior. Although adenosinergic signaling has been extensively investigated in the context of pain and neurological disorders, the specific contribution of A2AR to pain-related mechanisms is often addressed indirectly, as many studies focus on upstream neurobiological processes rather than nociception itself. In this narrative review, we integrate recent experimental, translational and observational evidence from in silico, in vitro, ex vivo, in vivo, and human studies to examine how A2AR-dependent signaling may influence mechanisms associated with pain modulation. The literature is organized according to conceptual and mechanistic criteria into four thematic axes: (i) neuroinflammation and central sensitization, (ii) astrocytic regulation and synaptic modulation, (iii) neurological disorders with pain-related components, and (iv) affective and emotional processes associated with the pain experience. Across these domains, convergent evidence suggests that A2AR signaling is involved in interactions between glial activation, inflammatory signaling, synaptic plasticity, and affective regulation. Together, these findings provide a framework for understanding how A2AR-related mechanisms contribute to process associated with chronic pain development and persistence, even in experimental contexts not explicitly designed to assess nociception. This integrative perspective supports further investigation of A2AR as a potential therapeutic target in chronic pain and related neuroinflammatory conditions.

Benzamide derivatives as allosteric ligands of the human and rat P2X7 receptor - Andrea Spinaci; Aleksei Smirnov; Beatrice Francucci; Michela Buccioni; Catia Lambertucci; Gabriella Marucci; Elena Adinolfi; Diego Dal Ben; Rosaria Volpini (Purinergic Signalling, 2026)

Turning failure into success: how artificial intelligence can help personalize therapies and re-use patient data - Maria P. Abbracchio; Ernesto Damiani (Purinergic Signalling, 2026)
Despite robust preclinical evidence, many clinical trials, including several that targeted the purinergic system, fail to demonstrate efficacy in humans. Failure may stem from inability to accurately identify patient subgroups responding similarly to treatments. Here, we explore the potential of artificial intelligence to revolutionize how we group and classify patients in clinical studies. We introduce a new framework using Large Language Models-generated embeddings of detailed patient data, to create a semantic-aware latent space, enabling us to identify truly meaningful patients’ clusters. Large Language Models can provide explainable groupings, giving clear reasons why certain patients respond similarly to treatments. We present an example of successful application of this approach through the re-analysis of the AMARANTH clinical trial (NCT02245737, involving ~ 2200 patients and completed in 2018) testing Lanabecestat , a BACE1 inhibitor decreasing β-amyloid production in Alzheimer’s disease, for which traditional analysis reported no efficacy. As in the original trial, our simulation showed no overall benefit. However, re-analysis per patients’ clusters and subjects’ re-stratification by semantic similarities (shared symptom profiles, progression patterns) identified a patients’ subgroup in one of the clusters showing Lanabecestat-associated slower disease worsening, thus succeeding where the full trial had failed. By making a new therapy available to at least a subset of patients with a defined disease, this new approach may help maximize the return on drug development and reduce the burden on healthcare. Moreover, it will significantly improve the precision, efficiency and interpretability of clinical trials, paving the way for a new era of personalized medical treatments.

Nucleotide signaling in neutrophils: a key player in cancer dynamics - Jean Lucas Gutknecht da Silva; Jean Sévigny; Daniela Bitencourt Rosa Leal (Purinergic Signalling, 2026)
Neutrophils are key innate immune cells whose effector mechanisms are increasingly recognized as therapeutic targets in chronic inflammation and cancer. While highly heterogeneous and functionally versatile, they can also exacerbate inflammation and tissue damage, making precise modulation critical for homeostasis. Nucleotide signaling—including extracellular nucleotide-metabolizing enzymes and receptors for ATP, UTP, and adenosine—plays a central role in regulating neutrophil responses. Extracellular nucleotides influence adhesion, chemotaxis, and degranulation, with important implications in cancer. Neutrophil heterogeneity affects tumor progression through both pro- and antitumor mechanisms. This review summarizes these findings and highlights therapeutic strategies targeting nucleotide signaling to modulate neutrophil activity in cancer.

P2Y6 receptor in the superior cervical ganglion: a key mediator of post-myocardial ischemic sympathetic hyperexcitability via NF-κB mediated neuroinflammation - Lifang Zou; Changyi Li; Mingshuo He; Chenxi Li; Chengxu Chen; Xuexuan Yang; Shuangmei Liu (Purinergic Signalling, 2026)

Positive allosteric modulator activity of ginsenosides is restricted to P2X7 and P2X4 receptors - Elizabeth Allum; Leanne Stokes (Purinergic Signalling, 2026)
Positive allosteric modulators of P2X7 receptors hold promise as host-directed immune enhancers in intracellular infections. We have previously reported the use of protopanaxadiol ginsenosides as positive allosteric modulators of human, rat and mouse P2X7 receptors plus human P2X4 receptors, however, the effect of ginsenosides on other P2X receptors is unknown. Here, we screened a range of ginsenosides and related glycosides at hP2X1, hP2X2 and hP2X3 receptors expressed in HEK-293 cells utilising a membrane potential assay. Our results demonstrate the utility of the membrane potential assay across all P2X receptors and the lack of significant potentiation of ATP-induced responses at hP2X1, hP2X2 and hP2X3 receptors by ginsenosides and related glycosides. We report that S-Rg3 also acts as a positive allosteric modulator at hP2X4 receptors in addition to hP2X7 receptors. This information is important for determining the selectivity of ginsenoside positive allosteric modulators for P2X7 and P2X4.

The ATP–adenosine axis as a driver of tumor-associated macrophage reprogramming in colorectal cancer: mechanistic insights into immune evasion and therapeutic vulnerabilities - Abdullah Faisal Albukhari (Purinergic Signalling, 2026)

Purinergic modulation in Parkinson’s disease: the dual role of istradefylline in motor and cognitive outcomes - Mokhtar Rejili; Hayder M. Al-kuraishy; Ali I. Al-Gareeb; Ali K. Albuhadily; Majid S. Jabir; Mustafa M. Shokr; Gaber El-Saber Batiha (Purinergic Signalling, 2026)

Acute effects of a single electroacupuncture session on purinergic signaling and inflammatory markers in patients with chronic nonspecific low back pain: a pilot study - Jardel Cristiano Ecco; Vinicius Ansolin; Adinei Abadio Soares; Angela Makeli Kososki Dalagnol; Filomena Marafon; Francini Franscescon; Matheus Chimelo Bianchini; Débora Tavares de Resende e Silva (Purinergic Signalling, 2026)

The long march towards testing the adenosine receptor agonism hypothesis for human cerebroprotection: The story of the A1R/A3R receptor agonist AST-004 - Theodore E. Liston; William S. Korinek; Kenneth A. Jacobson; James D. Lechleiter (Purinergic Signalling, 2026)

The analgesic effect of electroacupuncture in alleviating paclitaxel-induced peripheral neuropathic pain and its possible mechanism relates to TLR4/P2X7-NLRP3 signaling pathway - Yuan-xi Zhou; Man-ni Wang; Juan-juan Xin; Jing-wei Tan; Xiao Sang; Yu-xue Zhao (Purinergic Signalling, 2026)

Increased P2X7 level does not affect anxiety or stress-coping behavior in male mice - Lidia Urbina-Treviño; Hao Tang; Iven-Alex von Mücke-Heim; Tobias Engel; Annette Nicke; Jan M. Deussing (Purinergic Signalling, 2026)
The P2RX7 gene has been linked to various neuropsychiatric disorders. In particular, the SNP rs2230912, which results in a glutamine-to-arginine substitution at position 460, has repeatedly been associated with mood disorders. Although this SNP per se does not affect receptor function, it tags a gain-of-function haplotype that has been shown to significantly enhance receptor activity. BAC-transgenic P2X7-reporter mice have proven to be valuable tools for monitoring P2X7 expression. Here, we exploited their capacity to simultaneously overexpress the receptor, thereby serving as gain-of-function models to assess the behavioral consequences of elevated P2X7 levels. We used the two currently available transgenic P2X7 reporter lines (sEGFP and P2X7-EGFP), which differ in their expression pattern, degree of overexpression, and co-expression of the neighbouring P2rx4 gene. Male sEGFP and P2X7-EGFP mice showed no alterations in general activity or in measures of anxiety-related or stress-coping behavior compared to their wild-type littermates. Only male P2X7-EGFP mice exhibited slightly delayed locomotor habituation to a novel environment. To what extent higher expression levels reflect enhanced receptor activity, as conveyed by the disease-associated gain-of-function haplotype, requires further investigation. Overall, these results indicate that P2X7 overexpression—whether at endogenous or ectopic sites, or in conjunction with P2X4—is not sufficient to substantially alter behavior of individually housed male mice under baseline conditions.

The P2X4-P2X7 purinergic axis in alcohol-related liver disease: from fibrogenesis to immunotherapy resistance - Zixuan Li; Jie Qiao; Ji Qiu (Purinergic Signalling, 2026)

Identification of the promoter region of the human P2RX7 gene - Luyao Liu; Yoshiteru Kagawa; Colin L. Masters; Stanley S. Stylli; Theo Mantamadiotis; Ben J. Gu (Purinergic Signalling, 2026)

Functional role of peripheral P2X3 receptor expression in trigeminal ganglion neurons: a microarray-based evaluation of the antagonist effect of P2X3 - Mika Ishikawa; Takehiro Yajima; Kentaro Mizuta; Tadasu Sato (Purinergic Signalling, 2026)

Guanosine contributes to rapid purinergic regulation of dopamine during ischemia - Moriah E. Weese-Myers; Alaa S. Abdelrazeq Hassan; Ashley E. Ross (Purinergic Signalling, 2026)
Purinergic modulation of neurotransmission is a primary strategy employed in rapid neuroprotection during and after ischemic stroke. While the contributions of adenosine and ATP to the purinome are well-documented, guanosine-based regulatory activity has remained under-investigated. In the ischemia-vulnerable CA1 region of the hippocampus, dopamine serves as both a neurotransmitter involved in long-term potentiation during memory acquisition and as a regulator focused on modulating glutamate activity. Dopamine has been suggested as a potential protective force against glutamate-induced excitotoxicity in early ischemia. Here, we investigate changes in dopamine signaling during ischemia and demonstrate that guanosine administration during injury has an immediate protective effect. We observe rapid suppression of dopamine release following ischemic insult that is completely restored with administration of a low micromolar dose of guanosine. Changes in dopamine signaling and short-term mRNA production further suggest that guanosine’s rapid regulatory role may be partially achieved through the adenosine A1 and A2a receptors and that it facilitates dopamine reuptake through the dopamine transporter DAT. We present the first evidence that guanosine plays a rapid regulatory role in dopamine neurotransmission and that it may function as a broad facilitator of neurotransmitter reuptake, diversifying our understanding of the purinome in ischemia.

Modulation of P2X7-driven purinergic signaling and NLRP3 inflammasome activation underlies the hepatoprotective effects of coenzyme Q10 against glyphosate-based herbicide exposure - Duygu Mutluay; Seda Yakut; Gözde Yücel Tenekeci; Rüveyda Hilal Akı; Barış Denk; Adem Kara (Purinergic Signalling, 2026)

P2X7 receptor mediates the anti-tumor effect of running on cervical cancer in mice - Hai-Yun Xiong; Rui Li; Xiu-Min Hu; Yi Zhang; Patrizia Rubini; Peter Illes; Yong Tang (Purinergic Signalling, 2026)
Previous studies have suggested that running exerts anti-tumor effects on various cancers through multiple pathways. It has been reported that the P2X7 receptor (P2X7R) may display anti-tumor activity in cervical cancer cells, and running can regulate P2X7R expression and function in mice. However, the specific impact of running on cervical cancer and whether its underlying mechanism is associated with the regulation of P2X7R levels remains to be elucidated. In this study, mice bearing U14 cervical cancer tumors were used as a model to explore the association between running and P2X7R in cervical cancer. The results showed that running significantly inhibited tumor progression in mice, accompanied by an increase in P2X7R protein expression in tumor tissues. Additionally, treatment with the P2X7R antagonist JNJ-47965567 alone or in combination with running intervention promoted tumor growth and attenuated the anti-tumor effect of running. In contrast, the P2X7R agonist BzATP alone or combined with running intervention exerted anti-tumor effects and enhanced the anti-tumor effect of running. In conclusion, the present findings suggest only a pharmacological association between P2X7R and the anti-tumor effect of running against cervical cancer progression, given that genetic validation was not performed in this study. The potential involvement of immune mechanisms remains an inference and requires further experimental validation. As a possible therapeutic target, P2X7R provides supportive data for the treatment of cervical cancer and the clinical exploration of running as an adjuvant intervention.

ATP and major affective disorders: the involvement of P2X receptors in pathophysiology - Simona Mattova; Patrik Simko; Elena Colzi; Erika Stammova; Nicol Urbanska; Maria Grigoroiu-Serbanescu; Elisabetta Coppi; Terezia Kiskova-Simkova (Purinergic Signalling, 2026)
P2X receptors, a family of ATP-gated ion channels, are increasingly recognized as key contributors to the pathophysiology of major depressive disorder. Among them, P2X7 plays a central role in stress-induced neuroinflammation by driving microglial activation, inflammasome signaling, and downstream reductions in BDNF and neuroplasticity. Additional P2X subtypes, including P2X4, further modulate neuronal and glial communication relevant to mood regulation. Evidence from animal models, human genetic studies, and early therapeutic trials supports the involvement of P2X signaling in depressive phenotypes and highlights P2X7 antagonists as promising candidates for novel antidepressant strategies. Overall, targeting P2X receptors offers a mechanistically distinct approach to understanding and treating depression.

Purinergic signaling in dengue infection: modulation of P2 receptors as a potential therapeutic strategy - Vitória C. de Melo; Kayla I. de Oliveira; Marina Kipper; Margarete D. Bagatini; Gilnei B. da Silva (Purinergic Signalling, 2026)
Dengue is a globally widespread arboviral disease characterized by an intense inflammatory response that may progress to severe clinical manifestations, such as dengue shock syndrome and hemorrhagic fever. The lack of effective treatments underscores the urgent need to identify new therapeutic targets. In this context, purinergic signaling—mediated by molecules such as ATP and adenosine—has emerged as a central regulator of immune, inflammatory, and vascular responses during dengue virus (DENV) infection. Activation of purinergic receptors, particularly P2X7, directly influences viral replication, cytokine release, and endothelial barrier integrity, potentially contributing either to viral control or to disease severity when dysregulated. This review synthesizes the main mechanisms by which the purinergic system contributes to dengue pathogenesis, emphasizing both its physiological and pathological roles. The molecular analysis indicates that purinergic signaling plays a pivotal role in both restricting and exacerbating viral infection. Therefore, its pharmacological modulation represents a promising avenue for developing innovative therapeutic strategies, particularly for preventing severe dengue outcomes.

Expression of purinergic receptor P2Y, G-protein coupled 2, is regulated by estrogen during the estrous cycle in mouse uterus - Joohee Kim; Minju Kang; Byeongseok Kim; Yeonju Suh; Jimin Lee; Sangok Park; Ok-Hee Lee; Man Ryul Lee; Kwon-Ho Hong; Hoi Chang Lee; Youngsok Choi (Purinergic Signalling, 2026)

P2X7 receptor-mediated cGAS-STING pathway activation underlies chronic stress-induced depressive-like behaviors - Xi-Meng He; Yi Zhang; Cui-Yuan Chen; Yu-Li Han Tang; Xuan Li (Purinergic Signalling, 2026)

Tumor growth inhibitory activity of the P2X7 receptor antagonist AZ10606120 in two cell lines of human glioblastoma - Michela Graziano; Silvia Bono; Michela Pizzoferrato; Chiara Ferraro; Flavia Grossi; Pierluigi Navarra; Maria Martire; Lucia Lisi (Purinergic Signalling, 2026)
Glioblastoma multiforme (GBM) is among the most aggressive and lethal primary brain tumors. P2X7 is a purinergic receptor overexpressed in GBM, whose activation can promote tumor growth. Two major splice variants of the P2X7 receptor, isoforms A and B, are expressed in GBM cells. In our study, both isoforms A and B were present in GBM cells, with a slight prevalence of isoform B expression in the U87MG cell line compared to the T98G cell line. In GBM cell cultures, we evaluated the effects of P2X7 receptor activation/inhibition on cell growth. Exposure of GBM cells to various concentrations of ATP did not alter cellular activity, whereas inhibition of the P2X7 receptor with the antagonist AZ10606120, but not with A740003, significantly reduced GBM cell viability and proliferation. The U87MG cell line, which expresses the B isoform more highly, was more sensitive to the antiproliferative effects of AZ10606120. To clarify the mechanisms of AZ10606120-induced tumor inhibition, we measured the expression of proteins involved in cell repair and survival processes. AZ10606120 induced an increase in caspase-3 and p21 expression, demonstrating that P2X7R blockade can induce tumor cell death, likely by apoptosis. AZ10606120 also stimulated interleukin-6 (IL-6) release in GBM cells and induced phosphorylation of CREB and STAT3. Blockade of P2X7R by AZ10606120 appears to activate a pro-tumor IL-6/STAT3 axis. Increased IL-6 secretion and activation of the CREB and STAT3 pathways are negative prognostic signs that highlight the need to combine P2X7R inhibition with AZ10606120 with other therapies.

Adenosine A2A receptors in the chorioid plexus are causal in mediating the development of hydrocephalus - Xing-Ying Ren; Yong Tang; Peter Illes (Purinergic Signalling, 2026)

Light flickering with 40 Hz causes analgesia via activation of a retina-amygdala pathway and the local release of adenosine - Wei Zhao; Yong Tang; Peter Illes (Purinergic Signalling, 2026)

Proteasomal-dependent endothelial P2Y6 receptor downregulation as an adaptive mechanism limiting monocyte adhesion during intestinal schistosomiasis - Nathalia F. Oliveira; Matheus M. L. V. Monteiro; Leticia D. Crepaldi; Robson Coutinho-Silva; Luiz Eduardo B. Savio; Claudia L. Martins Silva (Purinergic Signalling, 2026)
Schistosomiasis, a complex chronic intravascular parasitic disease caused by Schistosoma mansoni , triggers a multifaceted host immune response and drives endothelial cells toward a sustained proinflammatory phenotype. The dysfunctional endothelial cells are a hallmark event that contributes to intestinal and liver damage mainly due to an increased monocyte adhesion, but the elevated morbidity unveils the lack of knowledge about disease pathogenesis. Purinergic P2Y 6 receptor (P2Y 6 R) expression is induced in some inflammatory models; therefore, we hypothesized that endothelial P2Y 6 R contributes to monocyte adhesion and mesenteric inflammation in S. mansoni -infected mice. Our results show that, unlike control mice, P2Y 6 R stimulation failed to enhance monocyte adhesion to endothelial cells from infected animals. Molecular analyses using RT-qPCR and immunocytochemistry revealed significant downregulation of P2Y 6 R expression in endothelial cells from the infected group at both transcript and protein levels. Importantly, pretreatment with a proteasome inhibitor restored both P2Y 6 R expression and function, implicating proteasomal degradation as a key mechanism underlying receptor loss during infection. Elevated lipid peroxidation in endothelial cells from the infected group further supported a role for reactive oxygen species (ROS)-dependent proteasome activation and receptor degradation. Collectively, these findings suggest that infection selectively modulates P2Y 6 R signaling by promoting proteasome-dependent downregulation of P2Y 6 R in endothelial cells, which could be an adaptive mechanism to reduce mesenteric inflammation and limit host tissue damage and morbidity during chronic infection. Graphical Abstract

Host-directed therapeutic strategies against apicomplexan parasites: targeting purinergic P2 receptors - Mariana M. Chaves; Nayara Carvalho-Barbosa; Luiz Eduardo Baggio Savio; Robson Coutinho-Silva (Purinergic Signalling, 2026)
Apicomplexan parasites establish intracellular infections that profoundly alter host cell physiology and elicit complex immune responses. The long-standing coevolution between these parasites and vertebrate hosts has resulted in extensive overlap between parasite and host metabolic pathways, limiting the feasibility of conventional parasite-centered therapeutic approaches. Increasing evidence indicates that host-derived signals generated during infection play a decisive role in shaping parasite survival and dissemination. Among these signals, extracellular nucleotides released in response to cellular stress and tissue damage have emerged as key modulators of innate immune responses. These molecules are sensed by purinergic P2 receptors, which integrate danger signals with inflammatory and microbicidal pathways. This review examines how purinergic signaling contributes to host–parasite interactions during apicomplexan infections, with particular emphasis on Toxoplasma gondii and Plasmodium spp. We discuss the dual role of P2 receptors in coordinating immune responses and directly affecting parasite viability, highlighting their potential as targets for host-directed therapeutic strategies.

Latest advances on the role of P2X Receptors in colorectal inflammation and cancer - Luigia Ruo; Federica Fortuna; Marianna Grignolo; Anna Pegoraro; Elena Adinolfi (Purinergic Signalling, 2026)
Extracellular adenosine triphosphate (eATP) is a hallmark of inflammatory and tumor-associated microenvironments, where it functions as a key extracellular signalling molecule through activation of purinergic receptors. In the gastrointestinal tract, and particularly in the colon, eATP-mediated signalling regulates epithelial barrier function, neuroimmune interactions, and immune responses. P2X receptors, a family of eATP-gated ion channels, are differentially expressed across epithelial, neuronal, and immune cell populations and are increasingly recognized as contributors to colonic pathophysiology. This review summarizes current evidence on the roles of P2X receptors in inflammatory bowel disease and colon carcinoma, highlighting their involvement in intestinal inflammation, visceral hypersensitivity, immune cell activation, and tumor-associated processes. We discuss how dysregulated P2X receptor signalling contributes to chronic inflammation and supports a tumor-promoting microenvironment, while also emphasizing the context- and cell-type-specific nature of these responses. Finally, we outline emerging therapeutic strategies targeting P2X receptors and underscore the importance of personalized approaches based on receptor expression patterns within the colonic tissue.

Mixed circuit training as a non-pharmacological strategy to improve platelet function and oxidative balance in type 2 diabetes: role of purinergic signaling - Lucas Macedo Chaves; Samantha Nuncio Prestes; André Campos De Lima; Aline Mânica; Daniela Zanini; Sedinei Lopes Copatti; Clodoaldo Antônio De Sá; Andréia Machado Cardoso (Purinergic Signalling, 2026)
This study investigates the impact of a 16-week mixed circuit training (MCT) program on purinergic signaling and oxidative stress markers in women with type 2 diabetes mellitus (T2DM), focusing on its potential to modulate platelet-related purinergic signaling and oxidative stress markers that are mechanistically linked to platelet activation. A total of 21 women with T2DM and 23 non-diabetic controls, all sedentary and middle-aged, underwent MCT twice weekly. Biochemical, hemodynamic, and oxidative stress parameters, along with platelet ectonucleotidase activity and extracellular ATP levels, were assessed pre- and post-intervention. MCT significantly decreased ectonucleotidase diphosphohydrolase (E-NTPDase) activity for ADP hydrolysis in platelets, along with a reduction in extracellular ATP levels, indicating a modulation of purinergic signaling. Additionally, exercise enhanced antioxidant defenses, increasing glutathione-S-transferase (GST) activity and vitamin C levels, while reducing myeloperoxidase (MPO) activity, a key pro-oxidant enzyme. These changes suggest a shift toward a biochemical profile that may be relevant to thromboinflammatory pathways; however, no direct measures of platelet aggregation were performed. Mixed circuit training emerges as a valuable non-pharmacological strategy for improving oxidative balance and modulating purinergic markers in women with T2DM, warranting future studies including functional platelet assays and clinical outcomes.

Phenolic compounds and chemotherapeutic agents differentially regulate P2X receptor subtypes in malignant melanoma - Serkan Sen; Sefa Celik (Purinergic Signalling, 2026)

The P2X7 receptor/NLRP3 inflammasome signaling axis in sepsis: molecular mechanisms, organ-specific pathophysiology, and emerging therapeutic strategies - Hilal Üstündağ (Purinergic Signalling, 2026)

The biphasic regulatory effect of adenosine A2B receptor in ischemic brain injury and its therapeutic potential - Xu Rui; Wang Xi; Li Mengzhu; Su Peiwei; Liu Mudong; Zhu Chao; Luo Wanyu; Zhao Haijun (Purinergic Signalling, 2026)

The potential role of adenosinergic pathway and methylxanthines in Parkinson’s disease: Blowing in the wind or not - Alaa Ismail; Hayder M. Al-kuraishy; Ali I. Al-Gareeb; Ali K. Albuhadily; Luay M. Alkazmi; Abdullah Faisal Albukhari; Mustafa M. Shokr; Athanasios Alexiou; Marios Papadakis; Gaber El-Saber Batiha (Purinergic Signalling, 2026)

Extracellular ATP induces the proinflammatory phenotype transition of MH7A cells by activating P2X7 receptor - Chengxiang Wang; Jiayao Hao; Yan Liu; Haili Shen (Purinergic Signalling, 2026)

Modulation of immune responses by opioids through toll-like and P2X receptor signaling in COVID-19 - Mohammad Abbas Sheikholeslami; Siavash Parvardeh; Shiva Ghafghazi; Malek Zarei (Purinergic Signalling, 2026)

Purinergic P2X7 receptor signaling in anxiety: Roles of stress-related neuroinflammatory mechanisms and therapeutic horizons - Simranpreet Kaur; Vikash Kumar Giri; Khadga Raj Aran (Purinergic Signalling, 2026)

In tribute to Francesco Di Virgilio, a great scientist and a wonderful friend - Simonetta Falzoni; Anna Lisa Giuliani; Elena Adinolfi; Robson Coutinho-Silva; Peter Illes; Simon C. Robson; Yong Tang; Henning Ulrich; Charles Kennedy (Purinergic Signalling, 2026)
Francesco Di Virgilio, one of the giants of purinergic signalling, died suddenly on September 22, 2024, which is an immense loss to so many friends and colleagues and especially to his beloved wife, Dorianna. Here, 1 year on, we pay tribute to him and his immense contribution to our field. Francesco graduated in medicine from the University of Padova, Italy, in 1979, with what became a lifelong interest in inflammation. He then held post-doctoral positions at University College London, Padova University, and Columbia University, New York, where he became acquainted with P2X7 receptors. He then returned to Padova as an Associate Professor of Molecular Pathology before moving to the University of Ferrara in 1992, where he set up a world-leading lab that studied the roles and underlying cellular mechanisms of the action of P2X7 receptors in inflammatory pathologies. Francesco published over 370 peer-reviewed articles, which have been cited > 35,000 times, giving him an H-index > 100. In addition, he filed several patents related to purinergic signalling. He also collaborated extensively, both within the University of Ferrara and worldwide, including in universities in the UK, Spain, Germany, the USA, and Brazil. Francesco was a man of great passion and intellect, who possessed scientific vision, intuition, and integrity, and he became the go-to world expert on P2X7 receptors and inflammation. We have lost a giant in the field and a dear friend, but he leaves behind an exceptional body of work, an outstanding legacy, and many friends who will miss him.

Tumor-driven purinergic signalling promotes RBFOX1 loss and chemotherapy-induced cardiotoxicity - Abdel-Aziz S. Shatat (Purinergic Signalling, 2026)

A2AR antagonist IDPU facilitates the restoration of mitochondrial dynamics in 6-OHDA-induced primary mid-brain neuronal cells, via regulating p38MAPK/Parkin/DJ-1/DRP1 axis - Vaishali Walecha; Jyoti Mishra; Tuithung Sophronea; Namrata Kumari; Pratibha Mehta Luthra (Purinergic Signalling, 2026)

Adenosine: potential target as rapid-acting antidepressants - Jia-Jia Li; Yong Tang; Peter Illes (Purinergic Signalling, 2026)

P2X4 receptors on myeloid cells mediate tissue injury in a model of trauma and hemorrhagic shock in male mice - Taha Kelestemur; Zoltán H. Németh; Pal Pacher; Burhan Yokus; H. Thomas Lee; Mihwa Kim; Mehmet S. Aydin; Ugur Akcan; György Haskó (Purinergic Signalling, 2026)

Brilliant blue G enhances cardiac function and suppresses ventricular arrhythmias by attenuating inflammation and fibrosis after post-myocardial infarction in rats - Zefei Jiang; Xuan Li; Masaomi Miura; Xiaoxiang Sun; Xiaohua Peng; Qiulian Lei; Rauza Sukma Rita; Yue Feng; Enxu Li; Xin Cao (Purinergic Signalling, 2026)

Expression of the P2X1 receptor remains in the type II spiral ganglion neurons in the mature rat cochlea - Prakansha N. Kumar; Srdjan M. Vlajkovic; Peter R. Thorne; Haruna Suzuki-Kerr (Purinergic Signalling, 2026)
Our sense of hearing commences in the cochlea, the peripheral sensory organ for hearing. Spiral ganglion neurons (SGN) in the cochlea are primary auditory neurons responsible for auditory neurotransmission. There are two classes of SGNs: type I SGNs, which make up 90-95% of the SGN population, and type II SGNs, which make up the remainder. Previous studies have shown that SGNs express a combination of purinergic (P2X, P2Y and adenosine) receptors at the mRNA and protein levels. In this study, we have focused on the P2X1 receptor to characterise its expression pattern in the Wistar rat cochlea at postnatal day 8 and in adult (6–8-week-old) rats of both genders using immunohistochemistry. Our results show differential expression of P2X1 receptors in 9.4-14.2% of SGNs in the adult cochlea, and 14.2-23.3% in the cochlea of P8 pups. In most of these neurons, P2X1 receptors were co-expressed with peripherin-1, an established type II SGN marker. These results suggest a potential role for the P2X1 receptor as a modulator of auditory neurotransmission in type II spiral ganglion neurons.

The purinergic signaling interfaces in breast cancer angiogenesis - Fernanda Cardoso da Silva; Jeferson Stabile; Cristina Ribas Fürstenau; Thaise Gonçalves Araújo (Purinergic Signalling, 2026)
Cancer is a group of diseases characterized by disordered cell proliferation and loss of tissue architecture. Breast cancer (BC) is the most common and lethal cancer among women, standing out for its molecular, histological and pathological heterogeneity. The BC tumor microenvironment (TME) is a complex ecosystem comprising transformed cells and a multitude of non-tumor cells, embedded in an altered extracellular matrix. Endothelial cells are present, driving angiogenesis, a relevant hallmark that ensures nutrition and oxygenation through the formation of new blood vessels. During this process, a complex network of molecules is released by tumor and endothelial cells, such as Vascular Endothelial Growth Factor (VEGF), that, in turn, induce cancer progression, diffusion, and metastasis. Purinergic signaling also regulates the functioning of endothelial cells involving the action of purines (ATP, ADP, UTP, UDP and adenosine) as signaling in purinergic receptors, with their concentration modulated by enzymes known as ectonucleotidases. This review aims to explore the contribution of purinergic signaling to BC angiogenesis, highlighting potential therapeutic targets currently under scientific focus. In general, the TME presents overexpression of ATP and adenosine, which stimulate endothelial cells through purinergic receptors. This stimulus promotes the formation of new vessels, mainly via the release of VEGF. Thus, purinergic signaling emerges as a central mechanism in BC angiogenesis, with potential to be explored in the development of antitumor therapies.

P2X4 receptors as the dynamic regulators of auditory sensory cell activity: a potential new mechanism for protecting hearing? - Alizée Fisher-Ridoux; Haruna Suzuki-Kerr (Purinergic Signalling, 2026)

Resistance exercise exerts anti-hypertensive effects and downregulates NTPDase/CD39 and ecto-5′-nucleotidase/CD73 expression in patients with chronic kidney disease undergoing hemodialysis - Angela Makeli Kososki Dalagnol; Francini Franscescon; Matheus Chimelo Bianchini; Josiano Guilherme Puhle; Keroli Eloiza Tessaro da Silva; Helamã Moraes Santos; Sarah Franco Vieira de Oliveira Maciel; Débora Tavares de Resende e Silva (Purinergic Signalling, 2026)
Chronic kidney disease (CKD) affects approximately 13.4% of the global population and significantly impacts patients’ quality of life. This study aimed to investigate the effects of resistance exercise on blood pressure and purinergic signaling in patients with CKD. Here, 28 patients with CKD performed a 12-week resistance exercise protocol during hemodialysis. Blood samples were collected before and after the intervention. Biochemical analyses, for example, NTPDases, ecto-5′-nucleotidase, and adenosine deaminase, were measured in platelets. Flow cytometry was performed to investigate CD39 and CD73 expression on lymphocytes. In addition, extracellular ATP and blood pressure were analyzed. Our findings revealed that patients with CKD present high systolic blood pressure ( p = 0.0002) compared to control, and resistance exercise reduces blood pressure in these patients ( p = 0.007). Regarding purinergic signaling, an increase in NTPDases, ecto-5′-nucleotidase, and adenosine deaminase was observed in patients with CKD ( p = 0.0001; p = 0.0001; p = 0.0001; p = 0.0007, respectively). Surprisingly, after resistance exercise, NTPDase/ATP and ecto-5′-nucleotidase decreased ( p = 0.0006; p = 0.02). CD39 and CD73 expression significantly increased on lymphocytes of CKD patients compared to control ( p = 0.004; p = 0.0002, respectively). After resistance exercise, CD39 and CD73 expression was downregulated. Extracellular ATP levels were decreased in CKD ( p = 0.0001), and resistance exercise restored these levels. In conclusion, CKD patients present high activity and expression of CD39 and CD73 enzymes, and resistance exercise mitigated purinergic exacerbation and presents anti-hypertensive effects in patients with CKD.

Spinal P2X3 receptors blockade reverses paclitaxel-induced allodynia in rats - Pedro Segura-Chama; Lucio Antonio Ramos-Chávez; Nashiely Yañez-Recendis; Francisco Pellicer; Martha León-Olea; Angélica Almanza; Francisco Mercado (Purinergic Signalling, 2026)

Abnormal purinergic signaling contributes to development of renal cysts in autosomal dominant polycystic kidney disease - Veniamin Ivanov; Andrew Wu; Letizia Crocetti; Ze Meng; Puja Shrestha-Maskey; Tang-Dong Liao; Indra Adrianto; Gabriella Guerrini; Pablo A. Ortiz; Tengis S. Pavlov (Purinergic Signalling, 2026)

Integrins α3 and α6 promote Th17 cell migration by activating the purinergic receptor P2X4 - Chakib Hamoudi; Anahita Lashgari; Fawzi Aoudjit (Purinergic Signalling, 2026)
Interactions of effector T cells with laminins during their trafficking across basement membranes play a crucial role in the development of the adaptive immune response and inflammatory diseases. However, the mechanisms involved in this process are not fully understood. In this study, we report that human Th17 cells express and use integrins α3 and α6 to migrate in laminin 10, which is predominant in basement membranes. We showed that laminin 10 induces via integrins α3 and α6, a sustained release of ATP from the mitochondria through pannexin-1 hemichannels, and that extracellular ATP is necessary for Th17 cell migration suggesting the implication of purinergic signaling. Inhibition studies identified a major role for the ionotropic purinergic receptor P2X4 in Th17 cell migration whereas purinergic receptors P2X7 and P2Y 11 had no role. Along these lines, our results showed that laminin 10 induced calcium entry into Th17 cells via the P2X4 receptor. Together these results show that integrins α3 and α6 induce Th17 cell migration by activating the P2X4 receptor. Our findings uncovered a crosstalk between laminin-binding integrins and purinergic signaling in promoting human Th17 cell migration and suggest that this pathway can play an important role in the immune response. Graphical Abstract This graphic shows how human Th17 cells migrate in laminin. Engagement of both laminin-binding integrins α3 and α6 by laminin 10 induces the release of ATP from the mitochondria through pannexin 1 channels. Extracellular ATP acts in an autocrine fashion to activate the purinergic receptor P2X4, which increases intracellular calcium. Calcium then enhances integrin activation and subsequently Th17 cell migration.

The role and therapeutic potential of purinergic signaling pathway in metabolic syndrome-related atherosclerosis - Xiang Li; Chengxin Gong; Chengxiao Fu; Qing Xia; Yue Zhang; Yue Du; Yuting Sun; Hong Xu (Purinergic Signalling, 2026)

Acupuncture alleviates postoperative hemorrhoid pain by modulating the P2X7/ERK pathway - Bin Chen; Tian Wang; Jie Gao; Yan Chen; Haijing Chang; Yi Shu; Yaling Zhang; Jiahuan Li; Guozhen Ma (Purinergic Signalling, 2026)

P2Y14 receptor activation and neutrophil signaling: linking inflammation to systemic pathophysiology - Renan da Silva Ebone; Pedro Henrique Doleski; Matheus Henrique Jantsch; Rafaella Pereira da Silveira; Daniela Bitencourt Rosa Leal (Purinergic Signalling, 2026)
Neutrophils are essential effector cells of the innate immune system, acting as the first line of defense against infection and tissue injury. Among the purinergic receptors expressed in these cells, P2Y14 has gained increasing attention in recent years for its role in modulating neutrophil recruitment and activation in inflammatory contexts. This receptor is activated mainly by uridine diphosphoglucose (UDP-glucose) and other UDP-sugars released during cellular stress or damage. Through the activation of G protein–coupled pathways, particularly via Gi/o and RhoA signaling, P2Y14 influences key neutrophil functions, including chemotaxis, cytoskeletal rearrangements, and oxidative responses. Despite its pro-inflammatory potential, and the increasing amount of literature data in recent years, P2Y14’s complete physiological and pathological roles remain underexplored. Literature data also highlight its involvement in diseases like glioblastoma and COVID-19, where, due to increased neutrophil infiltration, it exacerbates inflammation, tissue damage, and stress. Therefore, targeting P2Y14 may be a promising strategy to modulate neutrophil chemotaxis and mitigate unwanted harmful inflammatory responses. This review discusses the characteristics and signaling mechanisms of P2Y14 in neutrophils, as well as the relevant implications of this pathway for neutrophil function.

Adenosine A2A receptors in the nucleus accumbens regulate stress resilience and predict susceptibility to stress-induced affective disturbances - Laura Menegatti Bevilacqua; Francisco da Silveira Neto; Axel Fogaça Rosado; Cibele Martins Pinho; Nicolle Platt; Manuella P. Kaster (Purinergic Signalling, 2026)
Individual variability in stress responses contributes to susceptibility or resilience to mood and anxiety disorders. The adenosinergic system, particularly A1 and A2A receptors, modulates synaptic activity in brain regions involved in emotional regulation, including the nucleus accumbens (NAc), a central hub of reward processing and stress responsivity. Despite high adenosine receptor expression in the NAc, their specific role in stress resilience remains poorly understood. Here, we investigated the effects of 10 days of chronic social defeat stress (CSDS) on A1 and A2A receptor expression and synaptic proteins in the NAc of male C57BL/6 mice categorized as resilient (RES) or susceptible (SS) based on their sociability. SS mice exhibited social avoidance and elevated anxiety-like behaviors, whereas RES mice behaved comparably to controls. Neurochemical analyses revealed that RES mice had lower A2A receptor mRNA levels and decreased PSD-95 expression, suggesting reduced excitatory synaptic tone, while A1 receptor and gephyrin levels remained unchanged. To assess whether baseline adenosine signaling predicts stress vulnerability, we applied a caffeine responsiveness index. Caffeine, a non-selective adenosine receptor antagonist (7.5 mg/kg, i.p.), was used to classify Swiss mice as caffeine-responsive or non-responsive based on its psychostimulant effects, which are primarily attributed to A2A receptor antagonism. Following a 14-day washout, animals were exposed to chronic variable stress (CVS), and caffeine-responsive mice showed deficits in motivational and exploratory behaviors. Together, these findings indicate that lower A2A receptor signaling in the NAc supports stress resilience, whereas heightened baseline caffeine sensitivity may predict vulnerability to stress-induced affective disturbances. Graphical Abstract Reduced adenosine A2A receptor signaling in the nucleus accumbens (NAc) supports stress resilience, whereas heightened caffeine sensitivity predicts vulnerability. Under chronic social defeat stress, resilient mice display downregulated Adora2a mRNA and reduced PSD-95 levels, consistent with attenuated excitatory drive, while susceptible mice maintain A2A receptor activity and show anxiety-like behaviors. In the chronic variable stress paradigm, baseline caffeine responsiveness stratifies outcomes, with responsive mice presenting anxiety- and depressive-like behaviors, whereas mice there are non-responsive to caffeine exhibit disinhibited exploration but preserved motivation. Together, these findings identify baseline adenosine receptor signaling in the NAc as a key determinant of individual responses to chronic stress.

Capsaicin suppresses LPS-induced inflammatory responses via NLRP3/CASP-1/IL-1β axis and purinergic pathways in BV-2 microglial cells - Bianca Vedoin Copês Rambo; Milagros Fanny Vera Castro; Mairin Schott; Robson Lourenço da Silva Santos; Charles Elias Assmann; Marcylene Vieira da Silveira; Pâmela de Almeida Milioni; Adriel Antonio Schirmann; Vitor Bastianello Mostardeiro; Nathieli Bianchin Bottari; Maria Rosa Chitolina Schetinger; Vera Maria Melchiors Morsch (Purinergic Signalling, 2026)
Microglial activation drives neuroinflammation, a key factor in many neurological diseases. The purinergic system is a major regulator of inflammatory responses and represents a promising target for controlling neuroinflammation. Capsaicin, a bioactive compound found in chili peppers, exhibits significant anti-inflammatory and antioxidant properties. This study aimed to investigate the modulatory effects of capsaicin on microglial activation and purinergic system regulation. For this, BV-2 microglial cells were exposed to lipopolysaccharide (1 μg/mL) and treated with capsaicin (25 and 50 μM) for 24 hours. Cell viability was assessed by MTT and trypan blue assays. Cell cycle and apoptosis were evaluated by flow cytometry. Nitric oxide, reactive species and malondialdehyde levels were evaluated as markers of oxidative stress. Activities of NTPDase, 5'-nucleotidase (5’-NT), and adenosine deaminase (ADA) were evaluated. Gene expression of inflammatory mediators and purinergic receptors were analyzed by qRT-PCR, and molecular docking analyses were performed. As a result, capsaicin decreased the expression of pro-inflammatory mediators (NLRP3, CASP-1, IL-1β, IL-6, and TNF-α), increased IL-10 expression, and attenuated oxidative stress. It reduced NTPDase, 5'-NT, and ADA activities, downregulated P2X7 and A2A receptor expression, and upregulated A1 receptor expression. Molecular docking revealed that capsaicin has a high affinity for the A1 and A2A receptors, as well as for ADA. Collectively, these findings suggest that capsaicin exerts neuroprotective effect by suppressing pro-inflammatory signaling, enhancing anti-inflammatory responses, reducing oxidative stress, and modulating key components of the purinergic system, including ectoenzyme activities and P2X7, A1, and A2A receptor expression. Graphical Abstract Lipopolysaccharide (LPS) activates microglia via the NLRP3 pathway, increasing pro-inflammatory cytokines, purinergic receptors expression (P2X7 and A2A), and the activity of CD39, CD73, and ADA. Capsaicin mitigates this inflammatory profile by inhibiting NLRP3 signaling, reducing pro-inflammatory cytokine expression and modulating purinergic signaling toward an anti-inflammatory profile. Illustrations were obtained from Servier Medical Art ( https://smart.servier.com/ ), licensed under the Creative Commons Attribution 4.0 International License (CC BY 4.0).

Current understanding of ENaC regulation by P2Y2/PLC/PI(4,5)P2 pathway - Tarek Mohamed Abd El-Aziz; Ahmed Al-Sabi; Lucia A. Seale; Antonio G. Soares (Purinergic Signalling, 2026)

2025 World congress on purines—Chengdu, China - Peter Illes; Alexei Verkhratsky; Yong Tang (Purinergic Signalling, 2026)

Blockage of P2X7 receptor activation attenuated bone loss in ligature-induced model of periodontitis in rats - Nadine Linhares; Marco Aurelio Teófilo; Juliane Fernandes; Maria Jennifer Bernardino; Rachel Solidonio; Vanessa Sousa; Gisele Barreto; Everton da Silva; Ariana Maria Soares; Sthefane Feitosa; Denis Gonçalves; Delane Gondim; et al. (Purinergic Signalling, 2025)

Breast cancer patients present pro-tumor biomarkers related to purinergic signaling and oxidative stress - Eduarda Valcarenghi Jabonski; Simone Luciana Triquez; Ana Paula Geraldi Norbah; Daiane Manica; Keroli Eloiza Tessaro da Silva; Karlla Rackell Fialho Cunha; Nagilla Moreira Cordeiro; Marcelo Moreno; Débora Tavares de Resende e Silva; Sarah Franco Vieira de Oliveira Maciel (Purinergic Signalling, 2025)

The P2X7 receptor in leukemia: pathological mechanisms and therapeutic potential - Yanwen Xue; Xiaoxiang Peng; Meng Yan; Yanan Du; Yahui Cao; Ronglan Zhao (Purinergic Signalling, 2025)

Astrocytes: crucial transducers that convert norepinephrine inputs to ATP signaling in the brain - Yuto Kubota; Eiji Shigetomi; Bijay Parajuli; Schuichi Koizumi (Purinergic Signalling, 2025)

Adenine at lower doses acts in the kidney as an aquaretic agent and prevents hyponatremia - Alaa Alghamdi; Charuhas V. Thakar; Hassane Amlal (Purinergic Signalling, 2025)
We have previously reported that adenine at high doses interferes with the vasopressin signaling pathway, causes massive diuresis and volume depletion, and ultimately leads to renal failure. In the present study, we examined the effects of adenine on renal salt and water handling in a time course and dose–response study in rats housed in metabolic cages and fed control or adenine-containing diet at 1500, 2000, 2500 mg/kg and euthanized after 1, 3, and 7 weeks. Adenine at 2000 and 2500 mg/kg caused early and significant polyuria, polydipsia, and decreased urine osmolality in a dose-dependent manner without significantly affecting food intake, blood volume, blood electrolyte levels, or acid–base composition. The impaired water balance resulted from the downregulation of apical water channel AQP2 in the outer and inner medulla but not in the cortex. Adenine did not alter electrolytes (Na + , K + , Cl − ) excretion at these doses for up to 3 weeks. However, a slight but significant increase in salt excretion was observed in adenine-fed rats for 7 weeks, which correlates with a significant downregulation of NKCC2, mostly in rats fed 2500 mg/kg adenine. Adenine-fed rats exhibited a substantial resistance to vasopressin in response to water deprivation or vasopressin treatment. Lastly, 2500 mg/kg adenine prevented the development of hyponatremia in a rat experimental model of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). In conclusion, adenine acts as an aquaretic agent in the kidney at lower doses and during a short feeding period. It can be used as a vasopressin antagonist in conditions associated with hyponatremia.

The CALHM1 blocker CGP37157 increases seizure severity during status epilepticus in adult mice - Meghma Mitra; Amaya Sanz Rodriguez; Norman Delanty; Alan Beausang; Francesca M. Brett; Michael A. Farrell; Jane Cryan; Donncha F. O’Brien; David Henshall; Maria F. Cano-Abad; Tobias Engel (Purinergic Signalling, 2025)
Epilepsy is one of the most common chronic brain diseases affecting up to 70 million people worldwide. Major challenges of epilepsy treatment include the high pharmacoresistance in patients and the lack of disease-modification. Extracellular adenosine 3’triphosphate (ATP), a key neurotransmitter in the activation of the purinergic signalling system, is increasingly recognized to contribute to pathological brain hyperexcitability in epilepsy. Consequently, targeting ATP-release mechanisms may constitute a new therapeutic strategy for seizure control and epilepsy. The calcium channel, Calcium Homeostasis Modulator 1 (CALHM1), a voltage-gated, non-selective ion channel that permits the passage of various cations and small molecules, is expressed in neurons and plays an essential role during neuronal excitability and neurotransmission. In addition to ions, CALHM1 also allows the passage of ATP into the extracellular space, activating thereby purinergic receptors. Here, we tested if the pharmacological blocking of CALHM1 via CGP37157 (7-chloro-5-(2-chlorophenyl)-3,5-dihydro-4,1-benzothiazepin-2-(1H)-one) alters the severity of intra-amygdala kainic acid-induced status epilepticus. Our results show that CGP37157 increased the severity of seizures during status epilepticus. In addition, CALHM1 protein levels are down-regulated in the hippocampus in epileptic mice and Temporal Lobe Epilepsy (TLE) patients. In summary, our results identify CALHM1 as a new contributor to seizures and suggest targeting of CALHM1 as new treatment strategy for epilepsy.

Expanding the P2X7R toolbox: discovery of a novel Iodine-125 radioligand - Giorgia Tempra; Carlo Matera (Purinergic Signalling, 2025)

Macrophage P2Y6 receptor signalling as a key mediator and therapeutic target in atherosclerosis - Aida Collado; Zhichao Zhou (Purinergic Signalling, 2025)
Atherosclerosis, a chronic inflammatory disease driven by lipid deposition and immune cell activation, remains a leading cause of cardiovascular morbidity and mortality. Emerging evidence highlights the role of purinergic signalling in atherogenesis, particularly the P2Y 6 receptor in macrophages [1]. Using RNA sequencing, proteomics, expression and functional validation in cells, mouse models and human materials, this study provides comprehensive mechanistic insights into how macrophage P2Y 6 receptors contribute to foam cell formation and plaque development through the phospholipase Cβ (PLCβ)/store-operated Ca 2+ entry/calreticulin/scavenger receptor A (SR-A) pathway. Furthermore, the study identifies thiamine pyrophosphate (TPP) as a potent P2Y 6 receptor antagonist, effectively inhibiting foam cell formation and reducing plaque burden in atherosclerotic mice, without inducing toxicity. These findings establish P2Y 6 receptors as promising therapeutic targets in atherosclerosis and introduce TPP as a potential clinical candidate for intervention.

Editorial: Purinergic signalling—a perspective from China (II) - Yong Tang; Peter Illes (Purinergic Signalling, 2025)

Adenosine receptors and acute kidney injury: perspectives for future therapy - Isabela Berton Wissmann; Renata Cristina Daniel Coelho; Lilian Baseggio; Andreia Machado Cardoso (Purinergic Signalling, 2025)

Correction to: The role of purinergic P2X3 receptors and endometriosis-associated hyperalgesia - Kailane Paula Pretto; Letícia de Souza Matias; Bruna Dias de Oliveira; Adinei Abadio Soares; Camila Ferreira Puntel; Yghor Augusto da Rocha Ricardo; Yenidis Teilor Scheibel; Débora Tavares de Resende e Silva (Purinergic Signalling, 2025)

The role of purinergic P2X3 receptors and endometriosis-associated hyperalgesia - Kailane Paula Pretto; Letícia de Souza Matias; Bruna Dias de Oliveira; Adinei Abadio Soares; Camila Ferreira Puntel; Yghor Augusto da Rocha Ricardo; Yenidis Teilor Scheibel; Débora Tavares de Resende e Silva (Purinergic Signalling, 2025)

Acute effects of guanosine or inosine in a porcine model of hemorrhagic shock - André P. Schmidt; Denise A. Otsuki; Gisele Hansel; Jean P. Oses; Carolina D. Wiener; Fernanda P. Moreira; Luís V. Portela; Diogo O. Souza; Jose O. C. Auler (Purinergic Signalling, 2025)

Depletion of P2X4 receptor alleviates prostate cancer bone metastasis through reduced cancer cell invasiveness and enhanced cell adhesion activities - Jiepei He; Yuhan Zhou; Hector M. Arredondo Carrera; Nan Li; Alison Gartland; Ning Wang (Purinergic Signalling, 2025)
Prostate cancer (PCa) preferentially metastasizes to bone, which remains incurable and contributes significantly to mortality and morbidity. The P2X4 receptor (P2X4R) is a receptor for ATP that is highly expressed in many cancer types including PCa and is positively associated with tumorigenesis. To understand the role of P2X4R in PCa biology, particularly in PCa bone metastasis, P2X4R ( P2RX4 ) was knocked out in human PCa cell line PC3 cells using the CRISPR/Cas9 system. Cell proliferation, apoptosis, migration, and invasion were examined using CyQUANT, Cell Meter Caspase 3/7, scratch and transwell assays. Results showed that depleting P2X4R significantly reduced cell proliferation and invasion and increased apoptosis compared to PC3 wildtype (WT) controls in vitro. To test their metastatic potential in vivo, PC3 WT and knock-out (KO) cells were intracardiacally injected into male BALB/c immunocompromised mice. Twenty-five days post-injection, there were no detectable tumours and associated bone destruction in the tibias of mice injected with KO cells, whereas tibias of over 50% mice injected with WT cells were occupied by tumour cells, with significant bone destruction observed ex vivo using micro-CT. Furthermore, RNA-seq and bioinformatic analysis of P2X4R KO cells demonstrated links between P2X4R and PCa cell adhesion, and other key signalling such as Wnt signalling. These findings suggest that P2X4R is a potential therapeutic target for PCa metastasis, particularly bone metastasis.

ATP who you are - Yong Tang; Peter Illes (Purinergic Signalling, 2025)

P2 receptors signaling in the esophagus: from inflammation to cancer - Aline Zaparte; Fernanda F. Cruz; Julia B. de Souza; Fernanda B. Morrone (Purinergic Signalling, 2025)

Involvement of purinergic signalling in the vasomotor response to hypochlorous acid in porcine coronary artery - Ashwaq Baghdadi; William R. Dunn; Vera Ralevic (Purinergic Signalling, 2025)
Hypochlorous acid (HOCl) is generated by neutrophils during the innate immune response. ATP is released from cells by various stimuli and during inflammation but whether ATP is released by and participates in the response to HOCl is unclear. This study investigated vasomotor effects of HOCl on the porcine coronary artery (PCA) and the involvement of ATP and purine receptors. HOCl at 100 μM induced rapid and transient endothelium-dependent relaxation followed by slow and sustained endothelium-independent relaxation. Transient endothelium-dependent relaxation was induced by 500 μM HOCl, followed by endothelium-dependent contraction, then slow endothelium-independent relaxation. 8-(p-sulphophenyl)theophylline (8-SPT), an adenosine/P1 receptor antagonist, blocked rapid relaxation and contraction to HOCl but an A 2A receptor antagonist, ZM 241385, and an A 1 receptor antagonist, DPCPX, had no effect. Suramin, a P2 receptor antagonist (and membrane channel inhibitor), blocked rapid relaxation (at 100 μM HOCl) and contraction to HOCl. Other antagonists for P2, P2X1, P2Y1 and P2X4 receptors (PPADS, reactive blue 2, NF449, MRS2179 and BX430) did not affect HOCl responses. Relaxation to exogenous ATP was inhibited by 8-SPT but not by suramin suggesting that suramin block of HOCl responses may involve inhibition of membrane channels and endogenous ATP release. Apyrase, which hydrolyzes nucleotides, abolished responses to HOCl, ATP and unexpectedly adenosine. Neither probenecid nor carbenoxelone (connexin and pannexin channel inhibitors) blocked responses to HOCl. Luminescent ATP assay showed that HOCl elicited ATP release from cultures of human coronary artery endothelial cells. These findings advance our understanding of inflammation by showing that HOCl evokes endothelium-dependent vasorelaxation and contraction in coronary arteries which may involve P1 receptors implicating endogenous adenosine, possibly generated from rapid metabolism of ATP released by HOCl.

The anti-inflammatory effect of physical exercise on type 2 diabetes: the role of purinergic signaling - Andréia Machado Cardoso; André Campos de Lima; Aline Manica; Daniela Zanini; Lucas Macedo Chaves; Samantha Nuncio Prestes; Sedinei Lopes Copatti; Michele Mainardi Pillat; Taís Vidal; Clodoaldo Antônio de Sá (Purinergic Signalling, 2025)

A new approach to psoriasis therapy: photoswitchable A3 adenosine receptor activation - Federica Cherchi; Elisabetta Coppi (Purinergic Signalling, 2025)

Patients with periodontal disease demonstrates changes in purinergic and inflammatory markers in PBMCs, serum and saliva - Silviane Cunico Carneiro Füchter; Bárbara Stolarski; Daiane Manica; Eduardo Ottobelli Chielle; Débora Tavares de Resende e Silva; Sarah Franco Vieira de Oliveira Maciel (Purinergic Signalling, 2025)

Effects of nanoflubendazole and purinergic signaling modulation in overcoming neuroblastoma chemoresistance - Renata Siqueira de Mello; Carolina Adriane Bento; Rafael de Oliveira Faria; Vanessa Fernandes Arnaud-Sampaio; Henning Ulrich; Mariana Yasue Saito Miyagi; Gabriel Lima Barros de Araujo; Claudiana Lameu (Purinergic Signalling, 2025)

A step-by-step protocol based on data mining to explore purinergic signaling in glioblastoma - Martina Bedeschi; Ankita Agrawal; Elena Adinolfi; Anna Tesei; Valerie Vouret-Craviari (Purinergic Signalling, 2025)

T cell-derived adenosine regulates fibroblast IL-6 formation via A2B receptors in the infarcted heart - Tong Jiao; Zhichao Zhou (Purinergic Signalling, 2025)
Elevated interleukin-6 (IL-6) levels are linked to an increased risk of cardiovascular mortality in myocardial infarction (MI). Targeting IL-6 and its downstream signalling pathways represents a therapeutic strategy; however, its cellular sources and regulatory mechanisms of IL-6 remain incompletely understood. In this study, Alter and colleagues investigated the primary cell type that produces IL-6 in post-MI murine heart and the role of purinergic signalling in regulating IL-6 formation. Using cellular and mouse models, the authors identified cardiac fibroblasts as the predominant source of IL-6. Further analysis revealed that the IL-6 formation in cardiac fibroblasts is regulated by adenosine A 2B receptors. Of further importance, they elucidated that T cells highly express CD73, leading to significant adenosine formation, which in turn enhances IL-6 production via Gq activation in cardiac fibroblasts following MI. These findings reveal a dynamic interplay between immune cells and fibroblasts in shaping the post-MI inflammatory response. This study suggests the adenosine-A 2B receptor-IL6 axis as a potential therapeutic target to mitigate inflammation and improve cardiomyocytes salvage in MI.

Establishment and behavioural characterization of a novel constitutive P2X7 receptor knockout mouse line - Iven-Alex von Mücke-Heim; Judit Oldekamp; Michael W. Metzger; Sarah Kläffgen; Hao Tang; Sandra M. Walser; Nina Dedic; Gerhard Rammes; Florian Holsboer; Wolfgang Wurst; Jan M. Deussing (Purinergic Signalling, 2025)
The P2X7 receptor is an adenosine triphosphate (ATP)-gated ion channel expressed in different cell types of the brain. Polymorphisms in the P2RX7 gene have repeatedly been associated with psychiatric disorders including major depression. Depression is a stress-related disorder in which a dysregulation of the immune system has attracted increasing attention as a potential disease mechanism. The well-documented role of P2X7 in inflammatory conditions advocates its involvement in immune system dysregulation and depression genesis. However, understanding its exact role requires further research using appropriate animal models. Unfortunately, some of the most widely used P2X7 knockout mouse models are limited in their utility by the continuous expression of certain P2rx7 splice variants or even activation of de novo transcripts. To overcome this limitation, we generated a novel constitutive and complete P2X7 KO mouse line. These KO mice lack all known murine splice variants and protein expression resulting in a loss-of-function as confirmed by calcium imaging and by the inability of P2X7-deficient peritoneal macrophages to mount an appropriate interleukin (IL)-1β response. Comprehensive characterization using a battery of tests assessing locomotion, anxiety- and depression-related as well as social behaviour revealed differences in locomotor and exploratory behaviours. P2X7 KO mice showed slightly increased locomotor activity and reduced anxiety-related behaviour at baseline. Under conditions of chronic stress exposure, genotype-dependent differences largely dissolved while P2X7 deficiency promoted enhanced stress resilience with regard to social behaviour. Taken together, our findings add further evidence for an involvement of the P2X7 in shaping different behavioural responses and their modulation by stressful environments. This novel loss-of-function model will contribute to a better understanding of P2X7 in stress-associated behaviours in basic and translational neuropsychiatric research.

Combined oral contraceptives alter ectonucleotidase and adenosine deaminase activities in peripheral blood cells - Bruna Pache Moreschi; Romário da Silva Portilho; Andreza Negreli Santos; Igor Leal Brito; Jeandre Augusto Otsubo Jaques (Purinergic Signalling, 2025)

Reprogramming the tumor microenvironment by targeting cytidine deaminase in pancreatic ductal adenocarcinoma tumors: implications for the role of P2Y6 receptors - Abdel-Aziz S. Shatat (Purinergic Signalling, 2025)
Immunotherapies, such as immune checkpoint inhibitors (ICI), anti-cancer vaccines and adoptive T cell transfer, are promising treatments for cancer patients. However, ICI have not shown therapeutic benefit for most mismatch repair-proficient colorectal and pancreatic ductal adenocarcinoma tumors (PDAC), which are aggressive and deadly (Li et al. in Biomedicines 12:2175, 2024). Tumor metabolism can enhance immunological tolerance, but hinder immune cell function. In a recent publication in Nature Cancer , Scolaro et al. (Scolaro et al. in Nature Cancer 5:1206–1226, 2024) showed that cytidine deaminase (CDA) upregulation may play a crucial role in shaping the immunosuppressive landscape of human PDAC and other tumors. CDA targeting in pancreatic cancer cell lines led to reduced tumor growth, weight and total regression after treatment aimed at the programmed cell death protein 1 receptor (PD-1) immune checkpoint protein. CDA inhibition, both genetically and pharmacologically, overcame immunotherapy resistance in PDAC models. CDA targeting in PDAC cells altered the tumor microenvironment (TME), enabling T cells to respond to anti-PD-1. In mice with sgNT and sgCda tumors receiving anti-PD-1 treatment, they reduced the number of CD8 + T cells. CDA reduction in cancer cells makes tumors more sensitive to immunotherapy, presumably by overcoming immunosuppressive tumor-associated macrophages (TAMs) and forcing them to adopt an immunostimulatory phenotype. The study also found that cancer cells produce a TME rich in UDP (and UTP) by taking advantage of the CDA-mediated pyrimidine salvage pathway. This setting inhibits the recruitment and activation of CD8 + T cells by promoting the infiltration and immunosuppressive characteristics of P2Y 6 receptor–expressing TAMs.

Ligand-directed covalent labelling of adenosine receptors - Chloe Keduan Li; Karen Joan Gregory; Manuela Jörg (Purinergic Signalling, 2025)

First evidence of Tityus confluens Borelli, 1899 (Buthidae) venom altering purine metabolism in rat blood cells - Romário da Silva Portilho; Igor Leal Brito; Andreza Negreli Santos; Bruna Pache Moreschi; Malson Neilson de Lucena; Jeandre Augusto Otsubo Jaques (Purinergic Signalling, 2025)

Purinergic P2Y1 and P2Y12 receptors control enteric nervous system activity through neuro-glia-macrophage crosstalk - Blake J. Hendler; Jonathon L. McClain; Aurora Zilli; Luisa Seguella; Brian D. Gulbransen (Purinergic Signalling, 2025)

Therapeutic potential of P2X7 receptor in retinal diseases - Min Wen; Qin Xu; Jinfeng Xie; Rong Wu; Xiaomei Chen; Nianlian Wen; Sheng Huang (Purinergic Signalling, 2025)

Electroacupuncture alleviates capsaicin-induced rectal visceral pain in rats via inhibiting TRPV1 expression by blocking the P2X4R-activated p38 pathway - Yahong Xue; Qinbing Zhu; Jing Zhang; Xiaofeng Wang (Purinergic Signalling, 2025)

The enzymatic degradation of ATP to adenosine by microglial CD39 regulates neurovascular coupling and metabolic supply to the brain - Jing Guo; Yong Tang; Peter Illes (Purinergic Signalling, 2025)

P2X3 receptors in the paraventricular hypothalamus: a specific target for visceral pain - Xiu-Min Hu; Yong Tang; Peter Illes (Purinergic Signalling, 2025)

State of the art indicators for imaging purinergic dynamics in vitro and in vivo - Yumo Li; Liwan Zhang; Bohan Li; Yulong Li; Zhaofa Wu (Purinergic Signalling, 2025)

Role of macrophage ATP metabolism disorder in SiO2‑induced pulmonary fibrosis: a review - Hui-jie Hu; Yuan-yuan Fu; Shu-ling Du; Yu-han Zhang; Zhao-qiang Zhang; Gui-zhi Han (Purinergic Signalling, 2025)

The P2Y2 receptor: a new player in taste buds - Jian-Xiong Zhou; Yong Tang (Purinergic Signalling, 2025)

A2A receptors: a new target for immunotherapy resistance in prostate cancer - He-Xia Peng; Yong Tang (Purinergic Signalling, 2025)

P2Y6R together with CYSLTR2 serves as endogenous receptor for long-chain ceramides in atherosclerosis - Qing Ye; Yong Tang (Purinergic Signalling, 2025)

P2Y6 promoted pruning of FSTL1 nerves by cutaneous macrophages to reset pain threshold and cardiac function - Yun Liu; Xiao Sun; Zhengxu Jia; Qun Hou; Mingqian Yuan; Tiancheng Xu; Jinhong Yuan; Bin Xu; Zhi Yu (Purinergic Signalling, 2025)

SCH58261 effectively prevents the reduction in excitability of striatal MSNs in mice following 20 h of sleep deprivation - Jin Peng; Xinyu Huang; Peijie Liu; Yushi Hu; Liang Kang (Purinergic Signalling, 2025)

P2Y1R-IGFBP2 signaling: new contributor to astrocyte-neuron communication - Dan Huang; Yong Tang (Purinergic Signalling, 2025)

Antagonism of the ATP-gated P2X7 receptor inhibits the proliferation of hepatocellular carcinoma cells - Xinxing Tantai; Xin Yang; Xinyuan Liu; Xiao Yang (Purinergic Signalling, 2025)

CD39 activities in the treated acupoints contributed to the analgesic mechanism of acupuncture on arthritis rats - Yu-Jia Li; Jie Lin; Si-Qi Tang; Wei-Min Zuo; Guang-Hong Ding; Xue-Yong Shen; Li-Na Wang (Purinergic Signalling, 2025)

Electroacupuncture may alleviate inflammatory pain by downregulating the expression of P2Y14 receptor in the primary somatosensory cortex - Shuai Hou; Cui-Yuan Chen; Rui-Zhu Zhou; Liu-Xuan He; Xiao-Xiao Zhao; Sha-Sha Chen; Sha Yang; Hai-Yan Yin; Shu-Guang Yu (Purinergic Signalling, 2025)

The exploration of active components of 701 Dieda Zhentong patch and analgesic properties on chronic constriction injury rats - Jun Meng; Zhenglang Zhang; Yujie Wang; Lina Long; Anqi Luo; Zhenhui Luo; Kexin Cai; Xi Chen; Hong Nie (Purinergic Signalling, 2025)

Role of adenosine in the pathophysiology and treatment of attention deficit hyperactivity disorder - Qingxia Jia; Hongwan Tan; Tingsong Li; Xiaoling Duan (Purinergic Signalling, 2025)

Astrocytic P2X7 receptor regulates depressive-like behavioral reactions of mice in response to acute stressful stimulation - Xin-Yi Cheng; Wen-Jing Ren; Xuan Li; Jan M. Deussing; Peter Illes; Yong Tang; Patrizia Rubini (Purinergic Signalling, 2025)

Moxibustion pre-treatment attenuates seizure severity during status epilepticus and counteracts the proconvulsant function of the purinergic P2X7 receptor - Hong-Wei Zhang; Jia-Jia Li; Yulihan Tang; Mao-Lin Tian; Sheng Huang; Meng-Juan Sun (Purinergic Signalling, 2025)

Schwann cells transplantation improves nerve injury and alleviates neuropathic pain in rats - Wen-jun Zhang; Xi Li; Jun-xiang Liao; Dong-xia Hu; Song Huang (Purinergic Signalling, 2025)

Astrocytic P2X7 receptor in retrosplenial cortex drives electroacupuncture analgesia - Wei Zhao; Si-Le Liu; Si-Si Lin; Ying Zhang; Chang Yu (Purinergic Signalling, 2025)

Regulation of transcription factor function by purinergic signalling in cardiovascular diseases - Hao Tang; Qihang Kong; Zhewei Zhang; Wenchao Wu; Lixing Yuan; Xiaojing Liu (Purinergic Signalling, 2025)

Role of the P2X7 receptor in breast cancer progression - Yanan Du; Yahui Cao; Wei Song; Xin Wang; Qingqing Yu; Xiaoxiang Peng; Ronglan Zhao (Purinergic Signalling, 2025)

P2X7 and P2Y1 receptors in DRG mediate electroacupuncture to inhibit peripheral sensitization in rats with IBS visceral pain - Tingting Lv; Guona Li; Chen Zhao; Jindan Ma; Fang Zhang; Min Zhao; Huirong Liu; Huangan Wu; Kunshan Li; Zhijun Weng (Purinergic Signalling, 2025)

Microglial purinergic signaling in Alzheimer’s disease - Shu-Ya Mei; Ning Zhang; Meng-jing Wang; Pei-ran Lv; Qi Liu (Purinergic Signalling, 2025)

Role and recent progress of P2Y12 receptor in cancer development - Yanni Xi; Zhenya Min; Mianxue Liu; Xueqin Lin; Zhao-hua Yuan (Purinergic Signalling, 2025)

Caffeine: a potential mechanism for anti-obesity - Meng Wang; Wei Guo; Jiang-Fan Chen (Purinergic Signalling, 2025)

Functional role of P2X7 purinergic receptor in cancer and cancer-related pain - Yong-sheng Xu; Jun Xiang; Si-jian Lin (Purinergic Signalling, 2025)

CD73 polymorphisms are associated with schizophrenia - He-Xia Peng; Li-Li Zhang; Dan Jiang; Na Jian; Ting-Mei Zhang; Jia-Guo Luo; Hai-Yan Yin (Purinergic Signalling, 2025)
Ecto-5’-nucleotidase/CD73 enzyme plays a key role in the regulation of extracellular adenosine levels, thereby exerting influence on adenosine homeostasis. Emerging evidence suggests that perturbations in purines and ecto-5’-nucleotidase activity are associated with an augmented susceptibility to schizophrenia. However, the precise impact of genetic variations in CD73 on individuals with schizophrenia remains poorly understood. Here, our study demonstrated that rs3734442 allele and rs4431401 heterozygote were conferred a significant risk of schizophrenia disease (rs3734442: odds ratio, 0.556; 95% CI, 0.375 to 0.825; p = 0.004; rs4431401: odds ratio, 1.881, 95% CI, 1.117 to 3.166; p = 0.020). Comparing different genders, we observed a significant association between rs3734442 genotypes and male cases (rs3734442: odds ratio, 0.452; 95% CI, 0.257 to 0.796; p = 0.007). Likewise, there was a significant association between rs4431401 genotypes and male patients (rs4431401: odds ratio, 2.570; 95% CI, 1.196 to 5.522; p = 0.015). Based on family history and antipsychotics medication usage, our data reveals that the rs9444348 allele exhibits the most significant association with familial susceptibility to schizophrenia (odds ratio, 1.541; 95% CI, 1.009 to 2.353; p = 0.048 for A vs G). Moreover, individuals carrying variants of rs6922, rs2229523, and rs2065114 while being treated with clozapine demonstrate a higher frequency proportion compared to those receiving risperidone treatment ( p = 0.035; p = 0.049; p = 0.027 respectively). Additionally, our results indicate that patients with GG genotype of rs9444348 had significantly higher likelihood of using clozapine instead of sulpiride ( p = 0.048). Overall, our data strongly suggest that genetic variations in CD73 are significantly associated with schizophrenia risk and may serve as valuable resources for identifying therapeutic targets.

P2Y14 receptors: a new target for treating ulcerative colitis - Yan-Qin Zuo; Yong Tang (Purinergic Signalling, 2025)

P2X7 receptor is essential for ST36-attenuated cardiac fibrosis upon beta-adrenergic insult - Ting Zhang; Jing Lv; Zhong-yue Liu; Qiu-lian Lei; Ze-fei Jiang; Xiao-xiang Sun; Xing Yue; Xuan Li; Ke-li Zhu; Yun-kuan Yang; Ling Luo; Xin Cao (Purinergic Signalling, 2025)

P2X7 receptor: a potential target for treating comorbid anxiety and depression - Jun Liu; Ting-Ting Liu; Lan Mou; Yuwen Zhang; Xiang Chen; Qi Wang; Bin-Lu Deng; Jie Liu (Purinergic Signalling, 2025)
In clinical practice, depression and anxiety frequently coexist, and they are both comorbid with somatic diseases. The P2X7R is an adenosine 5’-triphosphate (ATP)-gated non-selective cation channel that is widely expressed in immune-related cells. Under conditions of stress, chronic pain, and comorbid chronic physical illness, P2X7R activation in glial cells leads to neuroinflammation. This could contribute to the development of anxiety and depression-related emotional disturbances. Previous studies have shown that the P2X7 receptor (P2X7R) plays an important role in the pathogenesis of both anxiety and depression. Thus, the P2X7R may play a role in the comorbidity of anxiety and depression. Positron emission tomography can be used to assess the degree and location of neuroinflammation by monitoring functional and expression-related changes in P2X7R, which can facilitate clinical diagnoses and guide the treatment of patients with anxiety and depression. Moreover, single nucleotide polymorphisms (SNPs) in the P2X7R gene are associated with susceptibility to different types of psychiatric disorders. Thus, evaluating the SNPs of the P2X7R gene could enable personalized mood disorder diagnoses and treatments. If the P2X7R were set as a therapeutic target, selective P2X7R antagonists may modulate P2X7R function, thereby altering the balance of intra- and extra-cellular ATP. This could have therapeutic implications for treating anxiety and depression, as well as for pain management. According to in vitro and in vivo studies, the P2X7R plays an important role in anxiety and depression. In this review, we consider the potential of the P2X7R as a therapeutic target for comorbid anxiety and depression, and discuss the potential diagnostic and therapeutic value of this receptor.

Purinergic P2X7 receptor involves in anti-retinal photodamage effects of berberine - Shan-Shan Ye; Jia-Ning Wang; Ya-Fei Zhao; Le-Shu Dai; Ji-Zhou Zhang; Yan-Qin Zuo; Jian-Tao Song (Purinergic Signalling, 2025)

The functional role of P2 purinergic receptors in the progression of gastric cancer - Fei-long Zou; Ji-peng Liu; Cheng Zuo; Peng-fei He; Jin-xiong Ye; Wen-jun Zhang (Purinergic Signalling, 2025)

Electroacupuncture regulates the P2X7R-NLRP3 inflammatory cascade to relieve decreased sensation on ocular surface of type 2 diabetic rats with dry eye - Mi-Mi Wan; Zhang-Yitian Fu; Tuo Jin; Zhuo-Yuan Wang; Xin-Yi Sun; Wei-Ping Gao (Purinergic Signalling, 2025)

Microbe-derived extracellular ATP via P2X7R signaling regulate macrophage heterogeneity in intestinal lymphoid tissue - Yu-Lihan Tang; Yong Tang (Purinergic Signalling, 2025)

Purinergic pathways and their clinical use in the treatment of acute myeloid leukemia - Huijuan Wang; Yujie Wei; Na Wang (Purinergic Signalling, 2025)

P2X7 receptors: a bibliometric review from 2002 to 2023 - Haiting Tang; Wei Wei; Yu Luo; Xiaoqing Lu; Jun Chen; Shenqiao Yang; Fei Wu; Haiyan Zhou; Wenbin Ma; Xin Yang (Purinergic Signalling, 2025)

Targeting adenosine A2A receptors for early intervention of retinopathy of prematurity - Xuhao Chen; Xiaoting Sun; Yuanyuan Ge; Xuzhao Zhou; Jiang-Fan Chen (Purinergic Signalling, 2025)

The role of purinergic signaling in acupuncture-mediated relief of neuropathic and inflammatory pain - Mingzhu Huo; Qingxiang Zhang; Yuxin Si; Youlin Zhang; Hongen Chang; Mengmeng Zhou; Di Zhang; Yuxin Fang (Purinergic Signalling, 2025)

P2 purinergic receptors regulate the progression of colorectal cancer - Wen-jun Zhang; Li-peng Zhang; Si-jian Lin; Cheng-yi Wang; Yi-guan Le (Purinergic Signalling, 2025)

Electroacupuncture may alleviate diabetic neuropathic pain by inhibiting the microglia P2X4R and neuroinflammation - Si-ying Qu; Han-zhi Wang; Qun-qi Hu; Yi-qi Ma; Yu-rong Kang; Li-qian Ma; Xiang Li; Lu-hang Chen; Bo-yu Liu; Xiao-mei Shao; Bo-yi Liu; Jun-ying Du; et al. (Purinergic Signalling, 2025)

A2B adenosine receptor-triggered intracellular calcium mobilization: Cell type-dependent involvement of Gi, Gq, Gs proteins and protein kinase C - Zhan-Guo Gao; Ray R. Gao; Clayton K. Meyer; Kenneth A. Jacobson (Purinergic Signalling, 2025)
Activation of PLCβ enzymes by G iβγ and G αq/11 proteins is a common mechanism to trigger cytosolic Ca 2+ increase. We and others reported that G αq/11 inhibitor FR900359 (FR) can inhibit both G αq - and, surprisingly, G iβγ -mediated intracellular Ca 2+ mobilization. Thus, the G αi -G βγ -PLCβ-Ca 2+ signaling axis depends entirely on the presence of active G αq , which reasonably explained FR-inhibited G iβγ -induced Ca 2+ 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 Ca 2+ increase triggered by native G q -coupled P2Y 1 receptors, or by transfected G i -coupled A 1 - 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 Ca 2+ increase triggered by native A 2B AR activation. Simultaneous inactivation of G i and G s further suppressed A 2B AR-triggered Ca 2+ increase in T24 cells. The G αq/11 inhibitor YM fully and partially inhibited endogenous P2Y 1 - and β 2 -adrenergic receptor-induced Ca 2+ increase in T24 cells, respectively. PKC activator PMA partially diminished A 2B AR-triggered but completely diminished β 2 -adrenergic receptor-triggered Ca 2+ increase in T24 cells. Neither β-arrestin1 nor β-arrestin2 siRNA affected A 2B AR-mediated Ca 2+ increase. Unlike in T24 cells, YM inhibited native A 2B AR-triggered calcium mobilization in MDA-MB-231 breast cancer cells. Thus, G αq/11 is vital for Ca 2+ increase in some cell types, but G iβγ -mediated Ca 2+ signaling can be Gα q/11 -dependent or independent based on cell type and receptor activated. Besides G proteins, PKC also modulates cytosolic Ca 2+ increase depending on cell type and receptor.

Extracellular ATP regulates phagocytic activity, mitochondrial respiration, and cytokine secretion of human astrocytic cells - Sijie Shirley Yang; Noah A. H. Brooks; Dylan E. Da Silva; Julien Gibon; Hashim Islam; Andis Klegeris (Purinergic Signalling, 2025)

The role of the P2X7 receptor in inactivated SARS-CoV-2-induced lung injury - 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 (Purinergic Signalling, 2025)

Mechanosensitive release of ATP in the urinary bladder mucosa - Violeta N. Mutafova-Yambolieva (Purinergic Signalling, 2025)

P2Y12 receptor-mediated cyclooxygenase 2 (COX-2) expression enhances tumor cell progression in a mouse model of lymphoma - Shilpa Sharma; Khagendra Ghimeray; Md. Mostafizur Rahman; Aparna Upadrasta; Ravi Shankar Akundi (Purinergic Signalling, 2025)

P2 purinergic receptor expression and function in tumor-related immune cells - Vahinipriya Manoharan; Oluwafemi O. Adegbayi; Janielle P. Maynard (Purinergic Signalling, 2025)

Purines and purinergic receptors in primary tumors of the central nervous system - Adinei Abadio Soares; Helamã Moraes dos Santos; Keyllor Nunes Domann; Natália Pratis Rocha Alves; Bernardo Ribeiro Böhm; Carolina Maliska Haack; Kailane Paula Pretto; Emily Sanini Guimarães; Guilherme Francisquini Rocha; Igor Rodrigues de Paula; Lucas Efraim de Alcântara Guimarães; Harlan Cleyton de Ávila Pessoa; et al. (Purinergic Signalling, 2025)

Promoting glymphatic flow: A non-invasive strategy using 40 Hz light flickering - Jianchen Fan; Zhihua Gao (Purinergic Signalling, 2025)

The P2X7R is a crucial target for Angiotensin II-induced myocardial ferroptosis and remodeling - Abdel-Aziz S. Shatat (Purinergic Signalling, 2025)
Ongoing cardiac remodeling can lead to negative outcomes, such as cardiac failure and diminished myocardial function, although the remodeling process initially protects the heart as a compensatory mechanism[1] . Importantly, ferroptosis appears to be a critical process in the development of cardiac disease. In a recent publication in Redox Biology , (Zhong et al. [2] showed that reactive oxygen species (ROS) generation and cardiac ferroptosis may be the mechanisms underlying angiotensin II (Ang II)-induced cardiac remodeling, as well as that ferroptosis is required for heart impairment and cardiac dysfunction induced by Ang II. Moreover, this study provides evidence that Ang II increases the expression of P2X7 receptors (P2X7R) in cardiac tissues and that both silencing and pharmacological inhibition of P2X7R significantly inhibited Ang II-induced ferroptosis and hypertrophy. Also, this work confirmed that P2X7R deficiency mitigated the Ang II-induced deterioration of cardiac injury in mice fed an iron-rich diet. Most interestingly, this study revealed that Ang II directly interacts with the P2X7R to activate and induce nucleocytoplasmic shuttling of human antigen R (HuR), which in turn controls the stability of the mRNA of heme oxygenase 1 (HO-1) and GPX4 and subsequent ROS production, which translated to induction of myocardial ferroptosis and remodeling.

Astrocytic adenosine A1 receptors: a new potential target for treating sepsis-associated encephalopathy - Si-Le Liu; Yong Tang (Purinergic Signalling, 2025)

Correction to: Adventures in translation - Bruce Cronstein; Siddhesh R. Angle (Purinergic Signalling, 2025)

Editorial—Translation of purinergic drugs into therapeutic use - Charles Kennedy (Purinergic Signalling, 2025)

Adventures in translation - Bruce Cronstein; Siddhesh R. Angle (Purinergic Signalling, 2025)

Honouring Geoff Burnstock - Yong Tang; Peter Illes; Charles Kennedy (Purinergic Signalling, 2025)

Screening herbal and natural product libraries to aid discovery of novel allosteric modulators of human P2X7 - Stefan Bidula; Waraporn Piyasirananda; Hanna Bielecka; Lučka Bibič; Andrew Beekman; Leanne Stokes (Purinergic Signalling, 2025)
P2X7 is an emerging therapeutic target for several disorders and diseases due to its role in inflammatory signalling. This study aimed to exploit the unique chemical libraries of plants used in traditional medicinal practices to discover novel allosteric modulators from natural sources. We identified several compounds from the NCI Natural Product library as P2X7 antagonists including confertifolin and digallic acid (IC 50 values 3.86 µM and 4.05 µM). We also identified scopafungin as a novel positive allosteric modulator of hP2X7. Screening a traditional medicinal plant extract library revealed 39 plant species with inhibitory action at hP2X7 and 17 plant species with positive allosteric modulator activity. Using computational docking to filter identified components from these plant species and determine potential antagonists, we investigated nine purified chemicals including flavonoids quercetin, kaempferol, ECG, and EGCG. These were shown to inhibit ATP-induced YO-PRO-1 uptake into HEK-hP2X7 cells; however, we also showed that all four flavonoids demonstrated significant assay interference using a cell-free DNA YO-PRO-1 fluorescence test. One plant extract, Dioscorea nipponica , demonstrating positive modulator activity was investigated, and dioscin was identified as a glycoside with PAM activity in ATP-induced YO-PRO-1 uptake assay and whole-cell patch-clamp recordings. However, membrane permeabilisation was observed following application > 10 min limiting the use of dioscin as a pharmacological tool. This work describes a useful workflow with multiple assays for the identification of novel allosteric modulators for human P2X7.

Astrocytic adenosine A2B receptors: a crucial player in brain function - Cui-Yuan Chen; Yong Tang (Purinergic Signalling, 2025)

Assessment of ATP metabolism to adenosine by ecto-nucleotidases carried by tumor-derived small extracellular vesicles - Chang-Sook Hong; Elizabeth V. Menshikova; Theresa L. Whiteside; Edwin K. Jackson (Purinergic Signalling, 2025)

Rosmarinic acid modulates purinergic signaling and induces apoptosis in melanoma cells - Gilnei B. da Silva; Daiane Manica; Paula Dallagnol; Rafael A. Narzetti; Filomena Marafon; Alana P. da Silva; Letícia de S. Matias; Joana V. Cassol; Marcelo Moreno; Aniela P. Kempka; Margarete D. Bagatini (Purinergic Signalling, 2025)

P2Y11 receptor is a critical regulator of extracellular ATP-mediated premature senescence in lung fibroblasts: Implications of ER-Ca+2 release/mitochondrial ROS production signaling pathway - Abdel-Aziz S. Shatat (Purinergic Signalling, 2025)

ENTPD1 (CD39) and NT5E (CD73) expression in human medulloblastoma: an in silico analysis - Marco Antônio Stefani; Elizandra Braganhol; Guilherme Tomasi Santos; Samuel Masao Suwa; Daiane Dias Cabeleira; Guilherme Pamplona Bueno de Andrade (Purinergic Signalling, 2025)

Identification of purinergic system components in the venom of Bothrops mattogrossensis and the inhibitory effect of specioside extracted from Tabebuia aurea - Dhébora Albuquerque Dias; Kamylla Fernanda Souza de Souza; Iluska Senna Bonfá Moslaves; Marcus Vinicius Buri; Denise Caroline Luiz Soares Basilio; Isabelly Teixeira Espinoça; Eduardo Benedetti Parisotto; Saulo Euclides Silva-Filho; Ludovico Migliolo; Jeandre Augusto Otsubo Jaques; Daniel Guerra Franco; Ana Marisa Chudzinski-Tavassi; et al. (Purinergic Signalling, 2025)

Ectonucleotidase inhibitors: targeting signaling pathways for therapeutic advancement—an in-depth review - R. Huzaifa Sharafat; Aamer Saeed (Purinergic Signalling, 2025)

Exploring novel dilazep derivatives as hENT1 inhibitors and potentially covalent molecular tools - Majlen A. Dilweg; Marina Gorostiola González; Martijn D. de Ruiter; Nadine J. Meijboom; Jacobus P. D. van Veldhoven; Rongfang Liu; Willem Jespers; Gerard J. P. van Westen; Laura H. Heitman; Adriaan P. IJzerman; Daan van der Es (Purinergic Signalling, 2025)
The human equilibrative nucleoside transporter 1 (SLC29A1, hENT1) is a solute carrier that modulates the passive transport of nucleosides and nucleobases, such as adenosine. This nucleoside regulates various physiological processes, such as vasodilation and -constriction, neurotransmission and immune defense. Marketed drugs such as dilazep and dipyridamole have proven useful in cardiovascular afflictions, but the application of hENT1 inhibitors can be beneficial in a number of other diseases. In this study, 39 derivatives of dilazep’s close analogue ST7092 were designed, synthesized and subsequently assessed using [ 3 H]NBTI displacement assays and molecular docking. Different substitution patterns of the trimethoxy benzoates of ST7092 reduced interactions within the binding pocket, resulting in diminished hENT1 affinity. Conversely, [ 3 H]NBTI displacement by potentially covalent compounds 14b , 14c , and 14d resulted in high affinities (K i values between 1.1 and 17.5 nM) for the transporter, primarily by the ability of accommodating the inhibitors in various ways in the binding pocket. However, any indication of covalent binding with amino acid residue C439 remained absent, conceivably as a result of decreased nucleophilic residue reactivity. In conclusion, this research introduces novel dilazep derivatives that are active as hENT1 inhibitors, along with the first high affinity dilazep derivatives equipped with an electrophilic warhead. These findings will aid the rational and structure-based development of novel hENT1 inhibitors and pharmacological tools to study hENT1's function, binding mechanisms, and its relevance in (patho)physiological conditions.

A2B adenosine receptor signaling and regulation - Zhan-Guo Gao; Mansour Haddad; Kenneth A. Jacobson (Purinergic Signalling, 2025)

Curcumin modulates purinergic signaling and inflammatory response in cutaneous metastatic melanoma cells - Daiane Manica; Gilnei Bruno da Silva; Rafael Antônio Narzetti; Paula Dallagnoll; Alana Patrícia da Silva; Filomena Marafon; Joana Cassol; Letícia de Souza Matias; Ariane Zamoner; Sarah Franco Vieira de Oliveira Maciel; Marcelo Moreno; Margarete Dulce Bagatini (Purinergic Signalling, 2025)

ATP release mediated by pannexin-3 is required for plasma cell survival via P2X4 receptors in bone marrow - Sonia Paz-López (Purinergic Signalling, 2025)

Purinergic signaling in health: special issue of purines 2022 in Brazil - Henning Ulrich; Carla I. Tasca; Claudiana Lameu (Purinergic Signalling, 2025)

P2X7 receptor in macrophage polarization and its implications in neuroblastoma tumor behavior - Carolina Adriane Bento; Vanessa Fernandes Arnaud-Sampaio; Talita Glaser; Elena Adinolfi; Robson Coutinho-Silva; Henning Ulrich; Claudiana Lameu (Purinergic Signalling, 2025)

Purinergic signaling in liver disease: calcium signaling and induction of inflammation - Henning Ulrich; Talita Glaser; Andrew P. Thomas (Purinergic Signalling, 2025)

Regulation of GABAergic neurotransmission by purinergic receptors in brain physiology and disease - Guilherme Juvenal; Guilherme Shigueto Vilar Higa; Lucas Bonfim Marques; Thais Tessari Zampieri; Felipe José Costa Viana; Luiz R. Britto; Yong Tang; Peter Illes; Francesco di Virgilio; Henning Ulrich; Roberto de Pasquale (Purinergic Signalling, 2025)

Partners in health and disease: pineal gland and purinergic signalling - Regina P. Markus; Kassiano S. Sousa; Henning Ulrich; Zulma S. Ferreira (Purinergic Signalling, 2025)

Lessons from the physiological role of guanosine in neurodegeneration and cancer: Toward a multimodal mechanism of action? - Carla Inês Tasca; Mariachiara Zuccarini; Patrizia Di Iorio; Francisco Ciruela (Purinergic Signalling, 2025)

How selective antagonists and genetic modification have helped characterise the expression and functions of vascular P2Y receptors - Markie O. Dales; Robert M. Drummond; Charles Kennedy (Purinergic Signalling, 2025)
Vascular P2Y receptors mediate many effects, but the role of individual subtypes is often unclear. Here we discuss how subtype-selective antagonists and receptor knockout/knockdown have helped identify these roles in numerous species and vessels. P2Y 1 receptor-mediated vasoconstriction and endothelium-dependent vasodilation have been characterised using the selective antagonists, MRS2179 and MRS2216, whilst AR-C118925XX, a P2Y 2 receptor antagonist, reduced endothelium-dependent relaxation, and signalling evoked by UTP or fluid shear stress. P2Y 2 receptor knockdown reduced endothelial signalling and endothelial P2Y 2 receptor knockout produced hypertensive mice and abolished vasodilation elicited by an increase in flow. UTP-evoked vasoconstriction was also blocked by AR-C118925XX, but the effects of P2Y 2 receptor knockout were complex. No P2Y 4 receptor antagonists are available and P2Y 4 knockout did not affect the vascular actions of UTP and UDP. The P2Y 6 receptor antagonist, MRS2578, identified endothelial P2Y 6 receptors mediating vasodilation, but receptor knockout had complex effects. MRS2578 also inhibited, and P2Y 6 knockout abolished, contractions evoked by UDP. P2Y 6 receptors contribute to the myogenic tone induced by a stepped increase in vascular perfusion pressure and possibly to the development of atherosclerosis. The P2Y 11 receptor antagonists, NF157 and NF340, inhibited ATP-evoked signalling in human endothelial cells. Vasoconstriction mediated by P2Y 12 /P2Y 13 and P2Y 14 receptors was characterised using the antagonists, cangrelor, ticagrelor, AR-C67085 and MRS2211 or PPTN respectively. This has yet to be backed up by receptor knockout experiments. Thus, subtype-selective antagonists and receptor knockout/knockdown have helped identify which P2Y subtypes are functionally expressed in vascular smooth muscle and endothelial cells and the effects that they mediate.

The impact of purine nucleosides on neuroplasticity in the adult brain - Beatriz dos Santos; Tetsade Piermartiri; Carla I. Tasca (Purinergic Signalling, 2025)

Cell cycle regulation by ADP and IGF-1 in cultured late developing glia progenitors of the avian retina - Isis Moraes Ornelas; Thayane Martins Silva; Mariana Rodrigues Pereira; Guilherme Rapozeiro França; Ana Lucia Marques Ventura (Purinergic Signalling, 2025)

Purinergic signaling in the battlefield of viral infections - Nayara Carvalho-Barbosa; Julianna Dias Zeidler; Luiz Eduardo Baggio Savio; Robson Coutinho-Silva (Purinergic Signalling, 2025)

Purinergic system in cancer stem cells - J. D. Nuñez-Rios; H. Ulrich; M. Díaz-Muñoz; C. Lameu; F. G. Vázquez-Cuevas (Purinergic Signalling, 2025)
Accumulating evidence supports the idea that cancer stem cells (CSCs) are those with the capacity to initiate tumors, generate phenotypical diversity, sustain growth, confer drug resistance, and orchestrate the spread of tumor cells. It is still controversial whether CSCs originate from normal stem cells residing in the tissue or cancer cells from the tumor bulk that have dedifferentiated to acquire stem-like characteristics. Although CSCs have been pointed out as key drivers in cancer, knowledge regarding their physiology is still blurry; thus, research focusing on CSCs is essential to designing novel and more effective therapeutics. The purinergic system has emerged as an important autocrine-paracrine messenger system with a prominent role at multiple levels of the tumor microenvironment, where it regulates cellular aspects of the tumors themselves and the stromal and immune systems. Recent findings have shown that purinergic signaling also participates in regulating the CSC phenotype. Here, we discuss updated information regarding CSCs in the purinergic system and present evidence supporting the idea that elements of the purinergic system expressed by this subpopulation of the tumor represent attractive pharmacological targets for proposing innovative anti-cancer therapies.

Preclinical evaluation of bozepinib in bladder cancer cell lines: modulation of the NPP1 enzyme - Álisson Coldebella da Silva; Juliete Nathali Scholl; Amanda de Fraga Dias; Augusto Ferreira Weber; Fernanda Bueno Morrone; Olga Cruz-López; Ana Conejo-García; Joaquín María Campos; Jean Sévigny; Fabrício Figueiró; Ana Maria Oliveira Battastini (Purinergic Signalling, 2025)

Hematopoietic stem cells on the crossroad between purinergic signaling and innate immunity - Stephanie Franczak; Henning Ulrich; Mariusz Z. Ratajczak (Purinergic Signalling, 2025)
Hematopoiesis is regulated by several mediators such as peptide-based growth factors, cytokines, and chemokines, whose biological effects have been studied for many years. However, several other mediators have been identified recently that affect the fate of hematopoietic stem/progenitor cells (HSPC) as well as non-hematopoietic cells in the bone marrow microenvironment. These new mediators comprise members of purinergic signaling pathways and are active mediators of the soluble arm of innate immunity, the complement cascade (ComC). In this review, we will discuss the coordinated effects of these pathways in regulating the biology of HSPC. Importantly, both purinergic signaling and the ComC are activated in stress situations and interact with specific receptors expressed on HSPC. Evidence has accumulated indicating that some of the purinergic as well as ComC receptors could also be activated intracellularly by intrinsically expressed ligands. To support this recent evidence, our work indicates that the major mediator of purinergic signaling, adenosine triphosphate, and the cleavage product of the fifth component of the ComC (C5), C5a anaphylatoxin, can activate their corresponding receptors expressed on the outer mitochondrial membrane in an autocrine manner. We will also discuss recent evidence that these responses, mediated by purinergic signaling and the ComC network, are coordinated by activation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 - reactive oxygen species - NLR family pyrin domain containing 3 (NLRP3) inflammasome (Nox2-ROS-NLRP3) axis.

Correction to: Preparation and preliminary evaluation of a tritium-labeled allosteric P2X4 receptor antagonist - Jessica Nagel; Olli Törmäkangas; Katja Kuokkanen; Ali El-Tayeb; Josef Messinger; Aliaa Abdelrahman; Christiane Bous; Anke C. Schiedel; Christa E. Müller (Purinergic Signalling, 2024)

Molecular mechanisms of extracellular-ATP-mediated colorectal cancer progression: Implication of purinergic receptors-mediated nucleocytoplasmic shuttling of HuR - Abdel-Aziz S. Shatat; Elsayed M. Mahgoup; Mohammed H. Rashed; Ibrahim G. Saleh; El-Sayed Akool (Purinergic Signalling, 2024)
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.

Preparation and preliminary evaluation of a tritium-labeled allosteric P2X4 receptor antagonist - Jessica Nagel; Olli Törmäkangas; Katja Kuokkanen; Ali El-Tayeb; Josef Messinger; Aliaa Abdelrahman; Christiane Bous; Anke C. Schiedel; Christa E. Müller (Purinergic Signalling, 2024)
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 [ 3 H]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. [ 3 H]PSB-OR-2020 may become a useful tool for research on P2X4 receptors and for promoting drug development.

Pharmacological differences between human and mouse P2X4 receptor explored using old and new tools - Anna Fortuny-Gomez; Samuel J. Fountain (Purinergic Signalling, 2024)
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.

Metastasis and angiogenesis in cervical cancer: key aspects of purinergic signaling in platelets and possible therapeutic targets - Paula C. L. Faria; Rackel S. Resende; Andréia M. Cardoso (Purinergic Signalling, 2024)

Unexpected role of microglia and P2Y12 in the induction of and emergence from anesthesia - Bijay Parajuli; Schuichi Koizumi (Purinergic Signalling, 2024)

Role of ecto-5’-nucleotidase in bladder function activity and smooth muscle contractility - Basu Chakrabarty; Bahareh Vahabi (Purinergic Signalling, 2024)

Purinergic regulation of pulmonary vascular tone - Marco Alveal; Andrea Méndez; Aline García; Mauricio Henríquez (Purinergic Signalling, 2024)

Gene expression alterations of purinergic signaling components in obesity-associated intestinal low-grade inflammation in type 2 diabetes - José R. Cruz-Muñoz; Eduardo E. Valdez-Morales; Alma Barajas-Espinosa; Tonatiuh Barrios-García; Andrómeda Liñán-Rico; Raquel Guerrero-Alba (Purinergic Signalling, 2024)

Machine learning-aided search for ligands of P2Y6 and other P2Y receptors - Ana C. Puhl; Sarah A. Lewicki; Zhan-Guo Gao; Asmita Pramanik; Vadim Makarov; Sean Ekins; Kenneth A. Jacobson (Purinergic Signalling, 2024)
The P2Y 6 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 P2Y 6 and subsequently P2Y 1 and P2Y 14 . Relying on extensive published data for P2Y 6 R 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 P2Y 6 R-induced functional calcium transients in transfected 1321N1 astrocytoma cells and fluorescent binding inhibition at closely related hP2Y 14 R expressed in CHO cells. The hit compound ABBV-744, an experimental anticancer drug with a 6-methyl-7-oxo-6,7-dihydro-1 H -pyrrolo[2,3- c ]pyridine scaffold, had multifaceted interactions with the P2YR family: hP2Y 6 R inhibition in a non-surmountable fashion, suggesting that noncompetitive antagonism, and hP2Y 1 R enhancement, but not hP2Y 14 R binding inhibition. Other machine learning-selected compounds were either weak (experimental anti-asthmatic drug AZD5423 with a phenyl-1 H -indazole scaffold) or inactive in inhibiting the hP2Y 6 R. Experimental drugs TAK-593 and GSK1070916 (100 µM) inhibited P2Y 14 R 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.

Cutaneous melanoma and purinergic modulation by phenolic compounds - Geórgia de Carvalho Braga; João Victor Coiado; Vitória Capelli de Melo; Brenno Bianchoni Loureiro; Margarete Dulce Bagatini (Purinergic Signalling, 2024)

Correction to: Role and recent progress of P2Y12 receptor in cancer development - Yanni Xi; Zhenya Min; Mianxue Liu; Xueqin Lin; Zhao-hua Yuan (Purinergic Signalling, 2024)

Role of CD73 and the purinergic signaling pathway in the pathogenesis of fusion-negative rhabdomyosarcoma - Amelia Fascì; Silvia Deaglio (Purinergic Signalling, 2024)

The P2Y2 receptor as a sensor of nucleotides and cell recruitment during inflammatory processes of the liver - Vinícius Santos Alves; Fabiana Cristina-Rodrigues; Robson Coutinho-Silva (Purinergic Signalling, 2024)

Implications of COVID-19 in Parkinson’s disease: the purinergic system in a therapeutic-target perspective to diminish neurodegeneration - Júlia Leão Batista Simões; Geórgia de Carvalho Braga; Samantha Webler Eichler; Gilnei Bruno da Silva; Margarete Dulce Bagatini (Purinergic Signalling, 2024)

Novel synthesized ionizable lipid for LNP-mediated P2X7siRNA to inhibit migration and induce apoptosis of breast cancer cells - Seyed Hossein Kiaie; Ali Rajabi Zangi; Mohammad Sheibani; Salar Hemmati; Behzad Baradaran; Hadi Valizadeh (Purinergic Signalling, 2024)

Genetic and functional modulation by agonist MRS5698 and allosteric enhancer LUF6000 at the native A3 adenosine receptor in HL-60 cells - Zhan-Guo Gao; Weiping Chen; Ray R. Gao; Jonathan Li; Dilip K. Tosh; John A. Hanover; Kenneth A. Jacobson (Purinergic Signalling, 2024)
The A 3 adenosine receptor (AR) is an important inflammatory and immunological target. However, the underlying mechanisms are not fully understood. Here, we report the gene regulation in HL-60 cells treated acutely with highly selective A 3 AR agonist MRS5698, positive allosteric modulator (PAM) LUF6000, or both. Both pro- and anti-inflammatory genes, such as IL-1a, IL-1β, and NFκBIZ, are significantly upregulated. During our observations, LUF6000 alone produced a lesser effect, while the MRS5698 + LUF6000 group demonstrated generally greater effects than MRS5698 alone, consistent with allosteric enhancement. The number of genes up- and down-regulated are similar. Pathway analysis highlighted the critical involvement of signaling molecules, including IL-6 and IL-17. Important upstream regulators include IL-1a, IL-1β, TNF-α, NF-κB, etc. PPAR, which modulates eicosanoid metabolism, was highly downregulated by the A 3 AR agonist. Considering previous pharmacological results and mathematical modeling, LUF6000’s small enhancement of genetic upregulation suggested that MRS5698 is a nearly full agonist, which we demonstrated in both cAMP and calcium assays. The smaller effect of LUF6000 on MRS5698 in comparison to its effect on Cl-IB-MECA was shown in both HL-60 cells endogenously expressing the human (h) A 3 AR and in recombinant hA 3 AR-expressing CHO cells, consistent with its HL-60 cell genetic regulation patterns. In summary, by using both selective agonists and PAM, we identified genes that are closely relevant to immunity and inflammation to be regulated by A 3 AR in differentiated HL-60 cells, a cell model of neutrophil function. In addition, we demonstrated the previously uncharacterized allosteric signaling-enhancing effect of LUF6000 in cells endogenously expressing the hA 3 AR.

Preclinical and clinical aspects of P2X receptors as a common route in different diseases: A meeting report - Luke Tattersall; Elena Adinolfi; Luca Antonioli; Ankita Agrawal (Purinergic Signalling, 2024)
PRESTO was established in 2022 and is a concerted effort by leading European experts in the field of P2XRs and extracellular ATP to promote and advance the transition to the clinic of P2XR-targeting therapies. Following the inaugural meeting in Ferrara which set the foundations of the action and generated interest from many groups and institutes, the second meeting covered the preclinical and clinical aspects of P2XRs as a common route in different diseases, recognising the multidisciplinary and collaborative approach required for a number of medical conditions.

Regulation of nerve-evoked contractions of the murine vas deferens - Pei Yee Wong; Zhihui Fong; Mark A. Hollywood; Keith D. Thornbury; Gerard P. Sergeant (Purinergic Signalling, 2024)
Stimulation of sympathetic nerves in the vas deferens yields biphasic contractions consisting of a rapid transient component resulting from activation of P2X1 receptors by ATP and a secondary sustained component mediated by activation of α 1 -adrenoceptors by noradrenaline. Noradrenaline can also potentiate the ATP-dependent contractions of the vas deferens, but the mechanisms underlying this effect are unclear. The purpose of the present study was to investigate the mechanisms underlying potentiation of transient contractions of the vas deferens induced by activation of α 1 -adrenoceptors. Contractions of the mouse vas deferens were induced by electric field stimulation (EFS). Delivery of brief (1s duration) pulses (4 Hz) yielded transient contractions that were inhibited tetrodotoxin (100 nM) and guanethidine (10 µM). α,β-meATP (10 µM), a P2X1R desensitising agent, reduced the amplitude of these responses by 65% and prazosin (100 nM), an α 1 -adrenoceptor antagonist, decreased mean contraction amplitude by 69%. Stimulation of α 1 -adrenoceptors with phenylephrine (3 µM) enhanced EFS and ATP-induced contractions and these effects were mimicked by the phorbol ester PDBu (1 µM), which activates PKC. The PKC inhibitor GF109203X (1 µM) prevented the stimulatory effects of PDBu on ATP-induced contractions of the vas deferens but only reduced the stimulatory effects of phenylephrine by 40%. PDBu increased the amplitude of ATP-induced currents recorded from freshly isolated vas deferens myocytes and HEK-293 cells expressing human P2X1Rs by 93%. This study indicates that: (1) potentiation of ATP-evoked contractions of the mouse vas deferens by α 1 -adrenoceptor activation were not fully blocked by the PKC inhibitor GF109203X and (2) that the stimulatory effect of PKC on ATP-induced contractions of the vas deferens is associated with enhanced P2X1R currents in vas deferens myocytes.

Molecular insights into P2X signalling cascades in acute kidney injury - Swati Mishra; Vishwadeep Shelke; Neha Dagar; Maciej Lech; Anil Bhanudas Gaikwad (Purinergic Signalling, 2024)

Limited contribution of the of P2X4 receptor to LPS-induced microglial reaction in mice - Nobili Paola; Ulmann Lauriane; Rassendren François; Hirbec Hélène (Purinergic Signalling, 2024)

Heterologous expression and biochemical characterization of the recombinant nucleoside triphosphate diphosphohydrolase 2 (LbNTPDase2) from Leishmania (Viannia) braziliensis - Nancy da Rocha Torres Pavione; João Victor Badaró de Moraes; Isadora Cunha Ribeiro; Raissa Barbosa de Castro; Walmir da Silva; Anna Cláudia Alves de Souza; Victor Hugo Ferraz da Silva; Raphael de Souza Vasconcellos; Gustavo da Costa Bressan; Juliana Lopes Rangel Fietto (Purinergic Signalling, 2024)

Deep learning structural insights into heterotrimeric alternatively spliced P2X7 receptors - Sophie K. F. De Salis; Jake Zheng Chen; Kristen K. Skarratt; Stephen J. Fuller; Thomas Balle (Purinergic Signalling, 2024)
P2X7 receptors (P2X7Rs) are membrane-bound ATP-gated ion channels that are composed of three subunits. Different subunit structures may be expressed due to alternative splicing of the P2RX7 gene, altering the receptor’s function when combined with the wild-type P2X7A subunits. In this study, the application of the deep-learning method, AlphaFold2-Multimer (AF2M), for the generation of trimeric P2X7Rs was validated by comparing an AF2M-generated rat wild-type P2X7A receptor with a structure determined by cryogenic electron microscopy (cryo-EM) (Protein Data Bank Identification: 6U9V). The results suggested AF2M could firstly, accurately predict the structures of P2X7Rs and secondly, accurately identify the highest quality model through the ranking system. Subsequently, AF2M was used to generate models of heterotrimeric alternatively spliced P2X7Rs consisting of one or two wild-type P2X7A subunits in combination with one or two P2X7B, P2X7E, P2X7J, and P2X7L splice variant subunits. The top-ranking models were deemed valid based on AF2M’s confidence measures, stability in molecular dynamics simulations, and consistent flexibility of the conserved regions between the models. The structure of the heterotrimeric receptors, which were missing key residues in the ATP binding sites and carboxyl terminal domains (CTDs) compared to the wild-type receptor, help to explain their observed functions. Overall, the models produced in this study (available as supplementary material) unlock the possibility of structure-based studies into the heterotrimeric P2X7Rs.