P2X7 is a member of the Ionotropic Purinergic Receptor (P2X) family. The P2X family of receptors is composed of seven (P2X1-7), ligand-gated, nonselective cation channels. Changes in P2X expression have been reported in multiple disease models. P2Xs have large complex extracellular domains that function as receptors for a variety of ligands, including endogenous and synthetic agonists and antagonists. ATP is the canonical agonist. ATP affinity ranges from nanomolar to micromolar for most P2XRs, but P2X7 has uniquely poor ATP affinity. In many physiological settings, it may be difficult to achieve the millimolar extracellular ATP concentrations needed for P2X7 channel activation; however, channel function is implicated in pain sensation, immune cell function, cardiovascular disease, cancer, and osteoporosis. Multiple high-resolution P2X7 structures have been solved in apo-, ATP-, and antagonist-bound states. P2X7 structural data reveal distinct allosteric and orthosteric antagonist-binding sites. Both allosteric and orthosteric P2X7 antagonists are well documented to inhibit ATP-evoked channel current. However, a growing body of evidence supports P2X7 activation by non-nucleotide agonists, including extracellular histone proteins and human cathelicidin-derived peptides (LL-37). Interestingly, P2X7 non-nucleotide agonism is not inhibited by allosteric antagonists, but is inhibited by orthosteric antagonists. Herein, we review P2X7 function with a focus on the efficacy of available pharmacology on P2X7 channel current activation by non-nucleotide agonists in effort to understand agonist/antagonist efficacy, and consider the impact of these data on the current understanding of P2X7 in physiology and disease given these limitations of P2X7-selective antagonists and incomplete knockout mouse models.

2024-12-01·Biochemical and Biophysical Research Communications

The P2X7 receptor mediates NADPH transport across the plasma membrane

Article

作者: Zhao, Yu-Zheng ; Hu, Li-Fang ; Wu, Jun-Chao ; Qin, Zheng-Hong ; Zhang, Rong ; Han, Rong ; Mou, Yu-Jie ; Zhang, Zhong-Ling ; Li, Feng-Min ; Sheng, Rui

Nicotinamide Adenine Dinucleotide Phosphate (NADPH) plays a vital role in regulating redox homeostasis and reductive biosynthesis. However, if exogenous NADPH can be transported across the plasma membrane has remained elusive. In this study, we present evidence supporting that NADPH can traverse the plasma membranes of cells through a mechanism mediated by the P2X7 receptor (P2X7R). Notably, we observed an augmentation of intracellular NADPH levels in cultured microglia upon exogenous NADPH supplementation in the presence of ATP. The P2X7R-mediated transmembrane transportation of NADPH was validated with P2X7R antagonists, including OX-ATP, BBG, and A-438079, or through P2X7 knockdown, which impeded NADPH transportation into cells. Conversely, overexpression of P2X7 resulted in an enhanced capacity for NADPH transport. Furthermore, transfection of hP2X7 demonstrated the ability to complement NADPH uptake in native HEK293 cells. Our findings provide evidence for the first time that NADPH is transported across the plasma membrane via a P2X7R-mediated pathway. Additionally, we propose an innovative avenue for modulating intracellular NADPH levels. This discovery holds promise for advancing our understanding of the role of NADPH in redox homeostasis and neuroinflammation.

2024-12-01·Neuropharmacology

P2X7 receptors modulate acquisition of cue fear extinction and contextual background memory generalization in male mice

Article

作者: Silva Júnior, Antonio Furtado da ; Moraes Resstel, Leonardo Barbosa ; Diniz, Cassiano Ricardo Alves Faria ; Domingos, Luana Barreto ; Terzian, Ana Luisa B. ; Terzian, Ana Luisa B ; Rosa, Jessica ; Resstel, Leonardo Barbosa Moraes

The purinergic P2X7 receptors (P2X7R) are activated by adenosine triphosphate (ATP) in several brain regions, particularly those involved with emotional control and the regulation of fear-related memories. Here, we investigate the role of P2X7R in fear learning memory, specifically in the acquisition and consolidation phases of the cued fear conditioning paradigm. C57Bl/6 wildtype (WT) male mice that received a single i.p. injection of the selective P2X7R antagonist A438079 prior the conditioning session showed generalization of cued fear memory and impaired fear extinction recall in the test session, while those treated prior the extinction session exhibited a similar behavior profile accompanied by resistance in the extinction learning. However, no effects were observed when this drug was administered immediately after the conditioning, extinction, or before the test session. Our results with P2X7R knockout (P2X7 KO) mice showed a behavioral profile that mirrored the collective effects observed across all pharmacological treatment conditions. This suggests that the P2X7R KO model effectively replicates the behavioral changes induced by the pharmacological interventions, demonstrating that we have successfully isolated the role of P2X7R in the fear and extinction phases of memory. These findings highlight the role of P2X7R in the acquisition and recall of extinction memory and supports P2X7R as a promising candidate for controlling abnormal fear processing, with potential applications for stress exposure-related disorders such as post-traumatic stress disorder (PTSD).

项与 P2X7R拮抗剂(Breye) 相关的新闻（医药）

2024-01-25

·PRNewswire

Breye Therapeutics Commences Oral Dosing of Danegaptide in Patients with Diabetic Retinopathy

Investigating potential for an oral treatment in diabetic retinopathy First patient dosed in Phase 1b/2a clinical trial COPENHAGEN, Denmark, Jan. 25, 2024 /PRNewswire/ -- Breye Therapeutics ApS (Breye), a clinical-stage biopharmaceutical company developing novel oral therapies for retinal vascular diseases within ophthalmology, today announces the start of a phase 1b/2a clinical trial to investigate danegaptide, following oral administration, in patients suffering from diabetic macular edema (DME). Breye is developing novel, oral ophthalmology drugs to address the need for more effective and less burdensome therapies for millions of patients suffering with deteriorating vision due to Diabetic Retinopathy (DR) or Age-Related Macular Degeneration (AMD). While there has been successful development of intravitreally administered products for patients with late-stage disease, treatment options are currently limited for patients in the early or moderate stages. As an oral therapy, danegaptide targets the core pathological events in DR, including cell-cell uncoupling, apoptotic vascular cell death and vascular leakage, at earlier stages of disease progression. With safety data derived from over 500 clinical trial participants, robust toxicology data, and strong non-clinical in vitro and in vivo efficacy results, there is strong support for danegaptide's potential to address the clinical core ocular pathologies of vascular leakage and capillary breakdown. The positive effects of treating these pathologies have been clinically validated. The study's design is a multicenter, open-label, dose-escalating Phase 1b/2a study to assess the safety, tolerability, pharmacokinetics (PK), and early signs of biological activity following oral administration of danegaptide in participants diagnosed with DME. Ulrik Mouritzen, Chief Executive Officer of Breye Therapeutics, said: "The launch of the Phase 1b/2a clinical trial for danegaptide represents a significant milestone towards realising our mission of developing more effective, globally accessible orally administered treatment solutions for patients at risk of vision loss and blindness. The burden on patients with diabetic retinopathy is significant and those who experience vision loss and blindness face threats to their physical and mental health and overall quality of life. At Breye, we are committed to help treat the disease earlier by offering effective oral therapies, to patients who currently have limited or no treatment options." Prof. Carl Regillo, MD, Director of Retina Service of Wills Eye Hospital and Professor of Ophthalmology at Thomas Jefferson University in Philadelphia, Member of the Breye Therapeutics Scientific Advisory Board, commented: "Danegaptide has the potential to become a valuable oral treatment option for patients with Diabetic Retinopathy. Patients should ideally be treated earlier and before the disease progresses to later stages, where laser treatments or intravitreally administered products are required." About Breye Therapeutics Breye is a biopharmaceutical company developing novel, oral ophthalmology drugs to address the needs of millions of patients suffering with deteriorating vision due to Diabetic Retinopathy (DR) or Age-Related Macular Degeneration (AMD), for which there are no treatments in early or moderate disease. Severe diabetic retinopathy requires intravitreal injections directly into the eye, which are unpopular with patients, resulting in a significant drop out rate of about 50% after 1 year and only 40% of patients obtain an optimal response. Orally administered drugs will be less burdensome than injections, as well as potentially more effective and commercially competitive. With its clinically de-risked safety profile, the lead program with danegaptide has potential for a short and well-accepted clinical regulatory pathway. Breye is also developing an oral P2X7R antagonist for AMD which seeks to reduce nerve damage and inflammation. Breye raised a seed round from Novo Holdings and Sound BioVentures and received financial support from the BioInnovation Institute, the Danish Growth Foundation (Vækstfonden) and the Danish Innovation Foundation (Innovationsfonden). For more information, please visit: SOURCE Breye Therapeutics

临床研究

100 项与 P2X7R拮抗剂(Breye) 相关的药物交易

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