Purinergic Signalling最新文献

The P2X7 receptor, an ATP-gated ion channel which belongs to the P2X receptor family, plays critical roles in recognizing extracellular adenosine 5'-triphosphate (ATP) and is widely expressed in most tumor cells as well as inflammatory cells. Previously, the P2X7 receptor has been demonstrated to modulate the progression of various malignancies, including glioblastoma, pancreatic cancer, lung cancer, leukemia, and lymphoma. However, the biological function and prognostic values of P2X7 receptor in hepatocellular carcinoma remain to be determined. Here, we investigated the expression level of P2X7 receptor in patients with hepatocellular carcinoma. Then MTS and EdU assays were carried out to study the role of P2X7 receptor blockade in the proliferation of hepatocellular carcinoma cells. In addition, the underlying mechanism was further elucidated by bulk RNAseq. Compared to the control group, the P2X7 receptor was significantly up-regulated in the hepatocellular carcinoma group. Interestingly, A740003 and A438079, two selective antagonists at P2X7 receptor, significantly blocked Ca²⁺ influx and decreased the proliferative rate of hepatocellular carcinoma cells. Furthermore, the expression level of chondroitin sulfate synthase 1 (CHSY1), an enzyme that mediates the polymerization step of chondroitin sulfate, was reduced by both A740003 and A438079. In conclusion, inhibition of the P2X7 receptor attenuated the proliferation of hepatocellular carcinoma cells, and this process was largely modulated by CHSY1. Thus, our findings reveal a previously unknown role for P2X7 receptor in the proliferation of hepatocellular carcinoma cells and imply that the P2X7 receptor may represent a new target for the treatment of hepatocellular carcinoma.

Adenosine, a sleep-associated neuromodulator, is crucial in various physiological and pathological processes. Previous studies have demonstrated that sleep deprivation (SD) alters striatal neuronal activity. In this study, we used in vitro electrophysiological recordings to investigate the effects of 20 h of SD on the neuronal excitability of mouse dorsal striatal medium spiny neurons (MSNs). Our findings revealed that SD resulted in altered action potential (AP) discharge properties and reduced neuronal excitability compared to the control group. Importantly, these changes were partially offset by the prophylactic injection of the A2A receptor (A2AR) antagonist SCH58261. Additionally, 20 h of SD caused a decrease in the amplitude and an increase in the interval of spontaneous excitatory postsynaptic currents (sEPSCs) compared to control. However, the prophylactic injection of the A2AR antagonism shortened the sEPSC interval, while the A1 receptor (A1R) antagonist DPCPX not only shortened the interval but also further reduced the amplitude of sEPSCs. Thus, it can be concluded that SCH58261 effectively prevents the reduction in excitability of striatal MSNs in mice following 20 h of sleep deprivation, whereas DPCPX does not.

Diabetic neuropathic pain (DNP) is a common and destructive complication of diabetes mellitus. The discovery of effective therapeutic methods for DNP is vitally imperative because of the lack of effective treatments. Although 2 Hz electroacupuncture (EA) was a successful approach for relieving DNP, the mechanism underlying the effect of EA on DNP is still poorly understood. Here, we established a rat model of DNP that was induced by streptozotocin (STZ) injection. P2X4R was upregulated in the spinal cord after STZ-injection. The upregulation of P2X4R was mainly expressed on activated microglia. Intrathecal injection of a P2X4R antagonist or microglia inhibitor attenuated STZ-induced nociceptive thermal hyperalgesia and reduced the overexpression of brain-derived neurotrophic factor (BDNF), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the spinal cord. We also assessed the effects of EA treatment on the pain hypersensitivities of DNP rats, and further investigated the possible mechanism underlying the analgesic effect of EA. EA relieved the hyperalgesia of DNP. In terms of mechanism, EA reduced the upregulation of P2X4R on activated microglia and decreased BDNF, IL-1β and TNF-α in the spinal cord. Mechanistic research of EA's analgesic impact would be beneficial in ensuring its prospective therapeutic effect on DNP as well as in extending EA's applicability.

P2Y12 receptor (P2Y12R) is an adenosine-activated G protein-coupled receptor (GPCR) that plays a central role in platelet function, hemostasis, and thrombosis. P2Y12R activation can promote platelet aggregation and adhesion to cancer cells, promote tumor angiogenesis, and affect the tumor immune microenvironment (TIME) and tumor drug resistance, which is conducive to the progression of cancers. Meanwhile, P2Y12R inhibitors can inhibit this effect, suggesting that P2Y12R may be a potential therapeutic target for cancer. P2Y12R is involved in cancer development and metastasis, while P2Y12R inhibitors are effective in inhibiting cancer. However, a new study suggests that long-term use of P2Y12R inhibitors may increase the risk of cancer and the mechanism remains to be explored. In this paper, we reviewed the structural and functional characteristics of P2Y12R and its role in cancer. We explored the role of P2Y12R inhibitors in different tumors and the latest advances by summarizing the basic and clinical studies on the effects of P2Y12R inhibitors on tumors.

Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease. The prevalent features of AD pathogenesis are the appearance of β-amyloid (Aβ) plaques and neurofibrillary tangles, which cause microglial activation, synaptic deficiency, and neuronal loss. Microglia accompanies AD pathological processes and is also linked to cognitive deficits. Purinergic signaling has been shown to play a complex and tight interplay with the chemotaxis, phagocytosis, and production of pro-inflammatory factors in microglia, which is an important mechanism for regulating microglia activation. Here, we review recent evidence for interactions between AD, microglia, and purinergic signaling and find that the purinergic P2 receptors pertinently expressed on microglia are the ionotropic receptors P2X4 and P2X7, and the subtypes of P2YRs expressed by microglia are metabotropic receptors P2Y₂, P2Y₆, P2Y₁₂, and P2Y₁₃. The adenosine P1 receptors expressed in microglia include A₁R, A_2AR, and A_2BR. Among them, the activation of P2X4, P2X7, and adenosine A₁, A_2A receptors expressed in microglia can aggravate the pathological process of AD, whereas P2Y₂, P2Y₆, P2Y₁₂, and P2Y₁₃ receptors expressed by microglia can induce neuroprotective effects. However, A₁R activation also has a strong neuroprotective effect and has a significant anti-inflammatory effect in chronic neuroinflammation. These receptors regulate a variety of pathophysiological processes in AD, including APP processing, Aβ production, tau phosphorylation, neuroinflammation, synaptic dysfunction, and mitochondrial dysfunction. This review also provides key pharmacological advances in purinergic signaling receptors.

Breast cancer is a common malignant tumor, whose incidence is increasing year by year, and it has become the malignant tumor with the highest incidence rate in women. Purine ligand-gated ion channel 7 receptor (P2X7R) is a cation channel receptor with Adenosine triphosphate ( ATP) as a ligand, which is widely distributed in cells and tissues, and is closely related to tumorigenesis and progression. P2X7R plays an important role in cancer by interacting with ATP. Studies have shown that P2X7R is up-regulated in breast cancer and can promote tumor invasion and metastasis by activating the protein kinase B (AKT) signaling pathway, promoting epithelial-mesenchymal transition (EMT), controlling the generation of extracellular vesicle (EV), and regulating the expression of the inflammatory protein cyclooxygenase 2 (COX-2). Furthermore, P2X7R was proven to play an essential role in the proliferation and apoptosis of breast cancer cells. Recently, inhibitors targeting P2X7R have been found to inhibit the progression of breast cancer. Natural P2X7R antagonists, such as rhodopsin, and the isoquinoline alkaloid berberine, have also been shown to be effective in inhibiting breast cancer progression. In this article, we review the research progress of P2X7R and breast cancer intending to provide new targets and directions for breast cancer treatment.

Acute stress causes depressive-like reactions in the tail suspension (TST) and forced swim tests (FST) of mice. Similarly, inescapable foot shock is able to promote the development of anhedonia as indicated by decreased sucrose consumption of treated mice in the sucrose preference test (SPT). The astrocyte-specific deletion of the P2X7R by a conditional knockout strategy or its knockdown by the intracerebroventricular (i.c.v.) delivery of an adeno-associated virus (AAV) expressing P2X7R-specific shRNA in astrocytes significantly prolonged the immobility time in TST and FST. In contrast, the shRNA-induced downregulation of the P2X7R in neurons, oligodendrocytes, or microglia had no detectable effect on the behavior of treated mice in these tests. Moreover, sucrose consumption in the SPT was not altered following inescapable foot shock treatment in any of these cell type-specific approaches. Immunohistochemistry indicated that the administered astrocyte-specific AAV efficiently conveyed expression of shRNA by hippocampal CA1 astrocytes, but not by neurons. In conclusion, P2X7R in astrocytes of this area of the brain appears to be involved in depressive-like reactions to acute stressors.

Our previous work had identified that at the acupuncture point (acupoint), acupuncture-induced ATP release was a pivotal event in the initiation of analgesia. We aimed to further elucidate the degradation of ATP by CD39. Acupuncture was administered at Zusanli acupoint on arthritis rats, and pain thresholds of the hindpaws were determined. Pharmacological tools or adeno-associated viruses were administered at the acupoints to interfere with targeting signals. Protein expression was determined with qRT-PCR, WB, or immunofluorescent labeling. Cultured keratinocytes, HaCaT line, were subjected to hypotonic shock to simulate needling stimulation. Extracellular ATP and adenosine levels were quantified using luciferase-luciferin assay and ELISA, respectively. Acupuncture-induced prompt analgesia was impaired by inhibiting CD39 activities to prevent the degradation of ATP to AMP but was mimicked by using CD39 agonists. Acupuncture-induced ATP accumulation exhibited synchronous changes. Similarly, acupuncture analgesia was hindered by suppressing CD73 to prevent the conversion of AMP to adenosine. Furthermore, the acupuncture effect was replicated by agonism at P2Y2Rs but inhibited by antagonism at them. Acupuncture upregulated CD73 and P2Y2Rs but not CD39. Immunofluorescent labeling demonstrated that keratinocytes were a primary site for these proteins. Shallow acupuncture also demonstrated antinociception. In vitro tests showed that hypotonic shock induced HaCaT cells to release ATP and adenosine, which was impaired by suppressing CD39 and CD73, respectively. Finally, agonism at P2Y2Rs promoted ATP release and [Ca²⁺]_i rise. CD39 at the acupoints contributes to the analgesic mechanism of acupuncture. It may facilitate adenosine signaling in conjunction with CD73 or provide an appropriate ATP milieu for P2Y2Rs. Skin tissue may be one of the scenes for these signalings.

Retinal diseases affect the health of millions of people worldwide and activated P2X7 receptors (P2X7Rs) are associated with the pathophysiology of a variety of retina-related diseases, including diabetic retinopathy, age-related macular degeneration, and glaucoma. Increasing evidence indicated that P2X7R is over-activated in retinopathy and is involved in the occurrence and development of diabetic retinopathy. Purine vasotoxicity caused by over-activation of P2X7R can lead to decreased retinal blood flow and vascular dysfunction and activation of P2X7R can lead to the production of a large number of inflammatory factors, causing local inflammatory cells to infiltrate and form a vascular microenvironment, thus constituting the pathophysiological basis for the occurrence and development of retinopathy. A variety of P2X7R antagonists have been studied in clinical trials as potential treatments for retinal diseases. However, currently no P2X7R antagonists has been approved for retina diseases. In this review, we mainly focus on recent progress on the involvement of P2X7R in retinal diseases and its therapeutic potential in the future.