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P2X4

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https://www.readbyqxmd.com/read/28428949/p2x1-p2x4-and-p2x7-receptor-knock-out-mice-expose-differential-outcome-of-sepsis-induced-by-%C3%AE-haemolysin-producing-escherichia-coli
#1
Anne-Sofie Greve, Marianne Skals, Steen K Fagerberg, Wulf Tonnus, Svend Ellermann-Eriksen, Richard J Evans, Andreas Linkermann, Helle A Praetorius
α-haemolysin (HlyA)-producing Escherichia coli commonly inflict severe urinary tract infections, including pyelonephritis, which comprises substantial risk for sepsis. In vitro, the cytolytic effect of HlyA is mainly mediated by ATP release through the HlyA pore and subsequent P2X1/P2X7 receptor activation. This amplification of the lytic process is not unique to HlyA but is observed by many other pore-forming proteins including complement-induced haemolysis. Since free hemoglobin in the blood is known to be associated with a worse outcome in sepsis one could speculate that inhibition of P2X receptors would ameliorate the course of sepsis...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/28413195/purinergic-signaling-in-microglia-in-the-pathogenesis-of-neuropathic-pain
#2
Kazuhide Inoue
Nerve injury often causes debilitating chronic pain, referred to as neuropathic pain, which is refractory to currently available analgesics including morphine. Many reports indicate that activated spinal microglia evoke neuropathic pain. The P2X4 receptor (P2X4R), a subtype of ionotropic ATP receptors, is upregulated in spinal microglia after nerve injury by several factors, including CC chemokine receptor CCR2, the extracellular matrix protein fibronectin in the spinal cord, interferon regulatory factor 8 (IRF8) and IRF5...
2017: Proceedings of the Japan Academy. Series B, Physical and Biological Sciences
https://www.readbyqxmd.com/read/28394853/targeting-bdnf-in-the-medial-thalamus-for-the-treatment-of-central-poststroke-pain-in-a-rodent-model
#3
Hsi-Chien Shih, Yung-Hui Kuan, Bai-Chung Shyu
Approximately 7-10% of patients develop a chronic pain syndrome after stroke. This chronic pain condition is called central poststroke pain (CPSP). Recent studies have observed an abnormal increase in the secretion of brain-derived neurotrophic factor (BDNF) in spinal cord tissue after spinal cord injury. An animal model of CPSP was established by an intra-thalamus injection of collagenase. Mechanical and thermal allodynia was induced after lesions of the thalamic ventral basal complex in rats. Four weeks after the injection, the number of neurons decreased, the number of astrocytes, microglia, and P2X4 receptors increased, and BDNF mRNA expression increased in the brain lesion area...
April 5, 2017: Pain
https://www.readbyqxmd.com/read/28360104/the-lysosomal-ca2-release-channel-trpml1-regulates-lysosome-size-by-activating-calmodulin
#4
Qi Cao, Yiming Yang, Xi Zoë Zhong, Xian-Ping Dong
Intracellular lysosomal membrane trafficking, including fusion and fission, is crucial for cellular homeostasis and normal cell function. Both fusion and fission of lysosomal membrane are accompanied by lysosomal Ca2+ release. We recently have demonstrated that the lysosomal Ca2+ release channel P2X4 regulates lysosome fusion through a calmodulin (CaM)-dependent mechanism. However, the molecular mechanism underlying lysosome fission remains uncertain. In this study, we report that enlarged lysosomes/vacuoles induced by either vacuolin-1 or P2X4 activation are suppressed by upregulating the lysosomal Ca2+ release channel transient receptor potential mucolipin 1 (TRPML1), but not the lysosomal Na+ release channel two pore channel 2 (TPC2)...
March 30, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28332633/structural-insights-into-the-nucleotide-base-specificity-of-p2x-receptors
#5
Go Kasuya, Yuichiro Fujiwara, Hisao Tsukamoto, Satoshi Morinaga, Satoshi Ryu, Kazushige Touhara, Ryuichiro Ishitani, Yuji Furutani, Motoyuki Hattori, Osamu Nureki
P2X receptors are trimeric ATP-gated cation channels involved in diverse physiological processes, ranging from muscle contraction to nociception. Despite the recent structure determination of the ATP-bound P2X receptors, the molecular mechanism of the nucleotide base specificity has remained elusive. Here, we present the crystal structure of zebrafish P2X4 in complex with a weak affinity agonist, CTP, together with structure-based electrophysiological and spectroscopic analyses. The CTP-bound structure revealed a hydrogen bond, between the cytosine base and the side chain of the basic residue in the agonist binding site, which mediates the weak but significant affinity for CTP...
March 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28306606/spinal-microglial-p2x4-receptor-brain-derived-neurotrophic-factor-signaling-regulates-nicotine-withdrawal-induced-hyperalgesia
#6
Xiaodi Zhang, Pengcheng Xu, Chengbao Li, Wenchao Zhu, Shanshan Wu, Ailan Yu, Yonghong Ding, Qinghe Wang, Zongwang Zhang
Nicotine withdrawal (NTW) has been shown to increase pain sensitivity. However, the pathogenesis of NTW-induced hyperalgesia syndrome is unknown. Microglial activation, with increased expression of the P2X4 receptor (P2X4R) and brain-derived neurotrophic factor (BDNF) as important markers, is associated with hyperalgesia; therefore, these markers may represent an unprecedented target to prevent hyperalgesia. In this study, we explored the contributions of spinal microglial P2X4R-BDNF signaling in NTW-induced hyperalgesia...
April 12, 2017: Neuroreport
https://www.readbyqxmd.com/read/28302727/intersubunit-physical-couplings-fostered-by-the-left-flipper-domain-facilitate-channel-opening-of-p2x4-receptors
#7
Jin Wang, Liang-Fei Sun, Wen-Wen Cui, Wen-Shan Zhao, Xue-Fei Ma, Bin Li, Yan Liu, Yang Yang, You-Min Hu, Li-Dong Huang, Xiao-Yang Cheng, Lingyong Li, Xiang-Yang Lu, Yun Tian, Ye Yu
P2X receptors are ATP-gated trimeric channels with important roles in diverse pathophysiological functions. A detailed understanding of the mechanism underlying the gating process of these receptors is thus fundamentally important and may open new therapeutic avenues. The left flipper (LF) domain of P2X receptors is a flexible loop structure and its coordinated motions together with the dorsal fin (DF) domain are crucial for the channel gating of the P2X receptors. However, the mechanism underlying the crucial role of the LF domain in the channel gating remains obscure...
March 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28280004/connexin-purinergic-signaling-in-enteric-glia-mediates-the-prolonged-effect-of-morphine-on-constipation
#8
Sukhada Bhave, Aravind Gade, Minho Kang, Kurt F Hauser, William L Dewey, Hamid I Akbarali
Morphine is one of the most widely used drugs for the treatment of pain. However, side effects, including persistent constipation and antinociceptive tolerance limit its clinical efficacy. Prolonged morphine treatment results in a "leaky" gut predisposing to colonic inflammation that is facilitated by microbial dysbiosis and associated bacterial translocation. In this study, we examined the role of enteric glia in mediating this secondary inflammatory response to prolonged treatment with morphine. We found that purinergic P2X receptor activity was significantly enhanced in enteric glia that were isolated from mice with long-term morphine treatment (in vivo) but not upon direct exposure of glia to morphine (in vitro)...
March 9, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28275350/blockade-of-p2x4-receptors-inhibits-neuropathic-pain-related-behavior-by-preventing-mmp-9-activation-and-consequently-pronociceptive-interleukin-release-in-a-rat-model
#9
Agnieszka M Jurga, Anna Piotrowska, Wioletta Makuch, Barbara Przewlocka, Joanna Mika
Neuropathic pain is still an extremely important problem in today's medicine because opioids, which are commonly used to reduce pain, have limited efficacy in this type of pathology. Therefore, complementary therapy is needed. Our experiments were performed in rats to evaluate the contribution of the purinergic system, especially P2X4 receptor (P2X4R), in the modulation of glia activation and, consequently, the levels of nociceptive interleukins after chronic constriction injury (CCI) of the right sciatic nerve, a rat model of neuropathic pain...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28237818/quercetin-inhibits-acid-sensing-ion-channels-through-a-putative-binding-site-in-the-central-vestibular-region
#10
Mohona Mukhopadhyay, Anurag Singh, S Sachchidanand, Amal Kanti Bera
Acid-sensing ion channels (ASICs) are associated with many pathophysiological processes, such as neuronal death during ischemic stroke, epileptic seizure and nociception. However, there is a dearth of ASIC-specific therapeutic blockers. Here we report that quercetin, a plant flavonoid, which is known for its neuroprotective effect, reversibly inhibits homomeric rat ASIC1a, ASIC2a and ASIC3 with an IC50 of about 2µM. Also, quercetin prevents low pH-induced intracellular calcium rise and cell death in HEK-293 cells, which have endogenous expression of ASIC1a and 2a...
February 22, 2017: Neuroscience
https://www.readbyqxmd.com/read/28235784/localization-of-the-gate-and-selectivity-filter-of-the-full-length-p2x7-receptor
#11
Anja Pippel, Michaela Stolz, Ronja Woltersdorf, Achim Kless, Günther Schmalzing, Fritz Markwardt
The P2X7 receptor (P2X7R) belongs to the P2X family of ATP-gated cation channels. P2X7Rs are expressed in epithelial cells, leukocytes, and microglia, and they play important roles in immunological and inflammatory processes. P2X7Rs are obligate homotrimers, with each subunit having two transmembrane helices, TM1 and TM2. Structural and functional data regarding the P2X2 and P2X4 receptors indicate that the central trihelical TM2 bundle forms the intrinsic transmembrane channel of P2X receptors. Here, we studied the accessibility of single cysteines substituted along the pre-TM2 and TM2 helix (residues 327-357) of the P2X7R using as readouts (i) the covalent maleimide fluorescence accessibility of the surface-bound P2X7R and (ii) covalent modulation of macroscopic and single-channel currents using extracellularly and intracellularly applied methanethiosulfonate (MTS) reagents...
March 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28192150/effect-of-artemisinin-on-neuropathic-pain-mediated-by-p2x4-receptor-in-dorsal-root-ganglia
#12
Mofeng Ying, Hui Liu, Tengling Zhang, Chenxu Jiang, Yingxin Gong, Bing Wu, Lifang Zou, Zhihua Yi, Shenqiang Rao, Guilin Li, Chunping Zhang, Tianyu Jia, Shanhong Zhao, Huilong Yuan, Liran Shi, Lin Li, Shangdong Liang, Shuangmei Liu
Neuropathic pain is a type of chronic pain caused by nervous system damage and dysfunction. The pathogenesis of chronic pain is complicated, and there are no effective therapies for neuropathic pain. Studies show that the P2X4 receptor expressed in the satellite glial cells (SGCs) of dorsal root ganglia (DRG) is related to neuropathic pain. Artemisinin is a monomeric component extracted from traditional Chinese medicine and has a variety of important pharmacological effects and potential applications. This study observed the effect of artemisinin on neuropathic pain and delineated its possible mechanism...
February 9, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28163685/ionotropic-p2x-atp-receptor-channels-mediate-purinergic-signaling-in-mouse-odontoblasts
#13
Yuta Shiozaki, Masaki Sato, Maki Kimura, Toru Sato, Masakazu Tazaki, Yoshiyuki Shibukawa
ATP modulates various functions in the dental pulp cells, such as intercellular communication and neurotransmission between odontoblasts and neurons, proliferation of dental pulp cells, and odontoblast differentiation. However, functional expression patterns and their biophysical properties of ionotropic ATP (P2X) receptors (P2X1-P2X7) in odontoblasts were still unclear. We examined these properties of P2X receptors in mouse odontoblasts by patch-clamp recordings. K(+)-ATP, nonselective P2X receptor agonist, induced inward currents in odontoblasts in a concentration-dependent manner...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28004813/electrical-stimulation-drives-chondrogenesis-of-mesenchymal-stem-cells-in-the-absence-of-exogenous-growth-factors
#14
Hyuck Joon Kwon, Gyu Seok Lee, Honggu Chun
Electrical stimulation (ES) is known to guide the development and regeneration of many tissues. However, although preclinical and clinical studies have demonstrated superior effects of ES on cartilage repair, the effects of ES on chondrogenesis remain elusive. Since mesenchyme stem cells (MSCs) have high therapeutic potential for cartilage regeneration, we investigated the actions of ES during chondrogenesis of MSCs. Herein, we demonstrate for the first time that ES enhances expression levels of chondrogenic markers, such as type II collagen, aggrecan, and Sox9, and decreases type I collagen levels, thereby inducing differentiation of MSCs into hyaline chondrogenic cells without the addition of exogenous growth factors...
December 22, 2016: Scientific Reports
https://www.readbyqxmd.com/read/28004778/glycosides-from-edible-sea-cucumbers-stimulate-macrophages-via-purinergic-receptors
#15
Dmitry Aminin, Evgeny Pislyagin, Maxim Astashev, Andrey Es'kov, Valery Kozhemyako, Sergei Avilov, Elena Zelepuga, Ekaterina Yurchenko, Leonid Kaluzhskiy, Emma Kozlovskaya, Alexis Ivanov, Valentin Stonik
Since ancient times, edible sea cucumbers have been considered a jewel of the seabed and used in Asian folk medicine for stimulation of resistance against different diseases. However, the power of this sea food has not been established on a molecular level. A particular group of triterpene glycosides was found to be characteristic metabolites of the animals, responsible for this biological action. Using one of them, cucumarioside A2-2 (CA2-2) from the edible Cucumaria japonica species as an example as well as inhibitory analysis, patch-clamp on single macrophages, small interfering RNA technique, immunoblotting, SPR analysis, computer modeling and other methods, we demonstrate low doses of CA2-2 specifically to interact with P2X receptors (predominantly P2X4) on membranes of mature macrophages, enhancing the reversible ATP-dependent Ca(2+) intake and recovering Ca(2+) transport at inactivation of these receptors...
December 22, 2016: Scientific Reports
https://www.readbyqxmd.com/read/28002740/the-dynamic-behavior-of-the-p2x4-ion-channel-in-the-closed-conformation
#16
Gustavo Pierdominici-Sottile, Luciano Moffatt, Juliana Palma
We present the results of a detailed molecular dynamics study of the closed form of the P2X4 receptor. The fluctuations observed in the simulations were compared with the changes that occur in the transition from the closed to the open structure. To get further insight on the opening mechanism, the actual displacements were decomposed into interchain motions and intrachain deformations. This analysis revealed that the iris-like expansion of the transmembrane helices mainly results from interchain motions that already take place in the closed conformation...
December 20, 2016: Biophysical Journal
https://www.readbyqxmd.com/read/27999370/effect-of-lead-pb-on-inflammatory-processes-in-the-brain
#17
REVIEW
Karina Chibowska, Irena Baranowska-Bosiacka, Anna Falkowska, Izabela Gutowska, Marta Goschorska, Dariusz Chlubek
That the nervous system is the main target of lead (Pb) has long been considered an established fact until recent evidence has linked the Pb effect on the immune system to the toxic effects of Pb on the nervous system. In this paper, we present recent literature reports on the effect of Pb on the inflammatory processes in the brain, particularly the expression of selected cytokines in the brain (interleukin 6, TGF-β1, interleukin 16, interleukin 18, and interleukin 10); expression and activity of enzymes participating in the inflammatory processes, such as cyclooxygenase 2, caspase 1, nitrogen oxide synthase (NOS 2) and proteases (carboxypeptidases, metalloproteinases and chymotrypsin); and the expression of purine receptors P2X4 and P2X7...
December 19, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27988461/divergent-regulatory-roles-of-extracellular-atp-in-the-degranulation-response-of-mouse-bone-marrow-derived-mast-cells
#18
Kazuki Yoshida, Masaaki Ito, Isao Matsuoka
Mast cells (MCs) play a critical role in allergic inflammation. Although purinergic signalling is implicated in the regulation of various immune responses, its role in MC function is not fully understood. In this study, we investigated the regulatory role of purinergic signalling in MC degranulation, using mouse bone marrow-derived mast cells (BMMCs). Notably, BMMCs expressed various functional P2 adenosine triphosphate (ATP) receptors, including ionotropic P2X4 and P2X7, involved in the regulation of BMMC degranulation...
February 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/27867013/characterization-of-p2x4-receptor-agonists-and-antagonists-by-calcium-influx-and-radioligand-binding-studies
#19
Aliaa Abdelrahman, Vigneshwaran Namasivayam, Sonja Hinz, Anke C Schiedel, Meryem Köse, Maggi Burton, Ali El-Tayeb, Michel Gillard, Jürgen Bajorath, Marc de Ryck, Christa E Müller
Antagonists for ATP-activated P2X4 ion channel receptors are currently in the focus as novel drug targets, in particular for the treatment of neuropathic and inflammatory pain. We stably expressed the human, rat and mouse P2X4 receptors in 1321N1 astrocytoma cells, which is devoid of functional nucleotide receptors, by retroviral transfection, and established monoclonal cell lines. Calcium flux assay conditions were optimized for high-throughput screening resulting in a Z'-factor of >0.8. The application of ready-to-use frozen cells did not negatively affect the results of the calcium assays, which is of great advantage for the screening of compound libraries...
November 17, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27823931/two-p2x1-receptor-transcripts-able-to-form-functional-channels-are-present-in-most-human-monocytes
#20
Cintya López-López, Josue Jaramillo-Polanco, Diana P Portales-Pérez, Karen S Gómez-Coronado, Jessica G Rodríguez-Meléndez, Juan D Cortés-García, Rosa Espinosa-Luna, Luis M Montaño, Carlos Barajas-López
To characterize the presence and general properties of P2X1 receptors in single human monocytes we used RT-PCR, flow cytometry, and the patch-clamp and the two-electrode voltage-clamp techniques. Most human monocytes expressed the canonical P2X1 (90%) and its splicing variant P2X1del (88%) mRNAs. P2X1 receptor immunoreactivity was also observed in 70% of these cells. Currents mediated by P2X1 (EC50=1.9±0.8µm) and P2X1del (EC50 >1000µm) channels, expressed in Xenopus leavis oocytes, have different ATP sensitivity and kinetics...
December 15, 2016: European Journal of Pharmacology
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