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Tomohiro Yamashita, Shota Yamamoto, Jiaming Zhang, Miho Kometani, Daisuke Tomiyama, Keita Kohno, Hidetoshi Tozaki-Saitoh, Kazuhide Inoue, Makoto Tsuda
P2X4 receptors (P2X4R) are a family of ATP-gated non-selective cation channels. We previously demonstrated that activation of P2X4R in spinal microglia is crucial for neuropathic pain, a highly debilitating chronic pain condition, suggesting that P2X4R is a potential therapeutic target for treating neuropathic pain. Thus, the identification of a compound that has a potent inhibitory effect on P2X4R is an important clinical challenge. In the present study, we screened a chemical library of clinically approved drugs and show for the first time that duloxetine, a serotonin and noradrenaline reuptake inhibitor, has an inhibitory effect on rodent and human P2X4R...
2016: PloS One
U Lalo, O Palygin, A Verkhratsky, S G N Grant, Y Pankratov
Recent studies highlighted the importance of astrocyte-secreted molecules, such as ATP, for the slow modulation of synaptic transmission in central neurones. Biophysical mechanisms underlying the impact of gliotransmitters on the strength of individual synapse remain, however, unclear. Here we show that purinergic P2X receptors can bring significant contribution to the signalling in the individual synaptic boutons. ATP released from astrocytes facilitates a recruitment of P2X receptors into excitatory synapses by Ca(2+)-dependent mechanism...
2016: Scientific Reports
Yuta Matsumura, Tomohiro Yamashita, Atsushi Sasaki, Eriko Nakata, Keita Kohno, Takahiro Masuda, Hidetoshi Tozaki-Saitoh, Toshiyasu Imai, Yasushi Kuraishi, Makoto Tsuda, Kazuhide Inoue
Accumulating evidence indicates that purinergic P2X4 receptors (P2X4R: cation channels activated by extracellular ATP) expressed in spinal microglia are crucial for pathological chronic pain caused by nerve damage, suggesting a potential target for drug discovery. We identified NP-1815-PX (5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1, 2-b][1,4]diazepine-2,4(3H,5H)-dione) as a novel antagonist selective for P2X4R with high potency and selectivity compared with other P2XR subtypes. In in vivo assay for acute and chronic pain, intrathecal administration of NP-1815-PX produced an anti-allodynic effect in mice with traumatic nerve damage without affecting acute nociceptive pain and motor function (although its oral administration did not produce the effect)...
2016: Scientific Reports
Wei Wang, Xiaosong Yi, Yanfang Ren, Qiufei Xie
INTRODUCTION: Adenosine 5'-triphosphate (ATP) is a potent signaling molecule that regulates diverse biological activities in cells. Its effects on human dental pulp cells (HDPCs) remain unknown. This study aimed to examine the effects of ATP on proliferation and differentiation of HDPCs. METHODS: Reverse transcription polymerase chain reaction was performed to explore the mRNA expression of P2 receptor subtypes. Cell Counting Kit-8 test and flow cytometry analysis were used to examine the effects of ATP on proliferation and cell cycle of HDPCs...
October 2016: Journal of Endodontics
Ji Xu, Alexander M Bernstein, Angela Wong, Xiao-Hong Lu, Sheraz Khoja, X William Yang, Daryl L Davies, Paul Micevych, Michael V Sofroniew, Baljit S Khakh
UNLABELLED: P2X4 receptors are ATP-gated cation channels that are widely expressed in the nervous system. To identify P2X4 receptor-expressing cells, we generated BAC transgenic mice expressing tdTomato under the control of the P2X4 receptor gene (P2rx4). We found sparse populations of tdTomato-positive neurons in most brain areas with patterns that matched P2X4 mRNA distribution. tdTomato expression within microglia was low but was increased by an experimental manipulation that triggered microglial activation...
August 24, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Karla Padilla, David Gonzalez-Mendoza, Laura C Berumen, Jesica E Escobar, Ricardo Miledi, Guadulupe García-Alcocer
Gene coding for ATP-gated receptor ion channels (P2X1-7) has been associated with the developmental process in various tissues; among these ion channel subtypes, P2X6 acts as a physiological regulator of P2X4 receptor functions when the two receptors form heteroreceptors. The P2X4 receptor is involved in pain sensation, the inflammatory process, and body homeostasis by means of Mg(2+) absorption through the intestine. The small intestine is responsible for the absorption and digestion of nutrients; throughout its development, several gene expressions are induced that are related to nutrients received, metabolism, and other intestine functions...
July 2016: Gene Expression Patterns: GEP
Sobia Manzoor, Umair Akhtar, Sidrah Naseem, Madiha Khalid, Misha Mazhar, Fahed Parvaiz, Saba Khaliq
Purinergic P2X receptors are plasma membrane bound, ATP-gated ion channels that are expressed on wide range of cells and respond to varying ATP concentrations in extracellular environment. Upon activation they increase membrane permeability for Ca(2+) ions and trigger a cascade of signaling complexes. During the course of hepatitis C virus (HCV) infection, ATP is released from the infected hepatocyte, which binds with Purinergic receptors (P2X) on peripheral blood mononuclear cells (PBMCs) and initiate downstream signaling pathways by disturbing the ionic balance of the cell...
September 2016: Viral Immunology
Yongxin Liang, Haichen Chu, Yanan Jiang, Li Yuan
Morphine creates a neuroinflammatory response and enhances release of the proinflammatory cytokines like interleukin-1β (IL-1β), which compromises morphine analgesia as well as induces morphine tolerance. In this study, we attempted to investigate the mechanisms of morphine induced IL-1β synthesis and release. Microglial cells were treated with morphine (100 μM) once daily for 3 days. Control groups underwent the same procedure but received sterile saline injection instead of morphine. Toll-like receptor 4 (TLR4) and P2X4 receptor (P2X4R) signaling were analyzed using Western blot; immunofluorescence was used to detect the signaling of CD68; real-time RT-PCR and ELISA kit was used to measure the messenger RNA and protein synthesis and release level of IL-1β...
August 9, 2016: Purinergic Signalling
Xi Zoë Zhong, Qi Cao, Xue Sun, Xian-Ping Dong
KEY POINTS: SLC17A9 proteins function as a lysosomal ATP transporter responsible for lysosomal ATP accumulation. P2X4 receptors act as lysosomal ion channels activated by luminal ATP. SLC17A9-mediated ATP transport across the lysosomal membrane is suppressed by Bafilomycin A1, the V-ATPase inhibitor. SLC17A9 mainly uses voltage gradient but not pH gradient generated by the V-ATPase as the driving force to transport ATP into the lysosome to activate P2X4. ABSTRACT: The lysosome contains abundant ATP which plays important roles in lysosome functions and in cell signalling...
August 1, 2016: Journal of Physiology
Jingyu Liu, Tino Prell, Beatrice Stubendorff, Silke Keiner, Thomas Ringer, Anne Gunkel, Vedrana Tadic, Nadine Goldhammer, Ayse Malci, Otto W Witte, Julian Grosskreutz
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder associated with intracellular Ca(2+) dysregulation. The P2X receptor family is comprised of ligand-gated ion channels that respond to extracellular adenosine triphosphate (ATP) and increases permeability of calcium into the cell. The underlying mechanisms of purinergic signalling on peripheral blood mononuclear cells (PBMCs) in ALS remain unclear. Herein, we studied the expression of P2X4/P2X7 receptors and calcium homeostasis in blood cells of ALS patients...
September 6, 2016: Neuroscience Letters
Sheraz Khoja, Vivek Shah, Damaris Garcia, Liana Asatryan, Michael W Jakowec, Daryl L Davies
Purinergic P2X4 receptors (P2X4Rs) belong to the P2X superfamily of ion channels regulated by ATP. We recently demonstrated that P2X4R knockout (KO) mice exhibited deficits in sensorimotor gating, social interaction, and ethanol drinking behavior. Dopamine (DA) dysfunction may underlie these behavioral changes, but there is no direct evidence for P2X4Rs' role in DA neurotransmission. To test this hypothesis, we measured markers of DA function and dependent behaviors in P2X4R KO mice. P2X4R KO mice exhibited altered density of pre-synaptic markers including tyrosine hydroxylase, dopamine transporter; post-synaptic markers including dopamine receptors and phosphorylation of downstream targets including dopamine and cyclic-AMP regulated phosphoprotein of 32 kDa and cyclic-AMP-response element binding protein in different parts of the striatum...
October 2016: Journal of Neurochemistry
Andrea Rivera, Ilaria Vanzulli, Arthur M Butt
The purine ATP has a prominent regulatory role in CNS function and pathology due to its actions on glial cells - microglia, astrocytes and oligodendrocytes. ATP serves as a ubiquitous 'gliotransmitter' that is released by astrocytes to activate purine receptors on neighbouring cells. In pathology, ATP release from glia and damaged cells mediates both tissue destruction and repair. The actions of ATP on glia are mediated via a wide range of receptors, broadly divided into ionotropic P2X and metabotropic (G-protein coupled receptors (GPCR) P2Y receptors, of which there are multiple subtypes (P2X1-P2X7 and P2Y1-P2Y14)...
July 11, 2016: Current Drug Targets
Aurore Besnard, Julien Gautherot, Boris Julien, Ali Tebbi, Isabelle Garcin, Isabelle Doignon, Noémie Péan, Emmanuel Gonzales, Doris Cassio, Brigitte Grosse, Bingkaï Liu, Hanaa Safya, Florent Cauchois, Lydie Humbert, Dominique Rainteau, Thierry Tordjmann
UNLABELLED: Many regulatory pathways are involved in liver regeneration after partial hepatectomy (PH), to initiate growth, protect liver cells, and sustain remnant liver functions. Extracellular adenosine triphosphate rises in blood and bile after PH and contributes to liver regeneration, although purinergic receptors and mechanisms remain to be precisely explored. In this work we analyzed during regeneration after PH the involvement of P2X4 purinergic receptors, highly expressed in the liver...
September 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Jeroen H F de Baaij, Andreas Kompatscher, Daan H H M Viering, Caro Bos, René J M Bindels, Joost G J Hoenderop
ATP-mediated signaling is an important regulator of electrolyte transport in the kidney. The purinergic cation channel P2X6 has been previously localized to the distal convoluted tubule (DCT), a nephron segment important for Mg2+ and Na+ reabsorption, but its role in ion transport remains unknown. In this study, P2x6 knockout (P2x6-/-) mice were generated to investigate the role of P2X6 in renal electrolyte transport. The P2x6-/- animals displayed a normal phenotype and did not differ physiologically from wild type mice...
2016: PloS One
Yung-Hui Kuan, Bai-Chuang Shyu
Painful sensations are some of the most frequent complaints of patients who are admitted to local medical clinics. Persistent pain varies according to its causes, often resulting from local tissue damage or inflammation. Central somatosensory pathway lesions that are not adequately relieved can consequently cause central pain syndrome or central neuropathic pain. Research on the molecular mechanisms that underlie this pathogenesis is important for treating such pain. To date, evidence suggests the involvement of ion channels, including adenosine triphosphate (ATP)-gated cation channel P2X receptors, in central nervous system pain transmission and persistent modulation upon and following the occurrence of neuropathic pain...
2016: Molecular Brain
Jimmy George, Rodrigo A Cunha, Christophe Mulle, Thierry Amédée
Recent data have provided evidence that microglia, the brain-resident macrophage-like cells, modulate neuronal activity in both physiological and pathophysiological conditions, and microglia are therefore now recognized as synaptic partners. Among different neuromodulators, purines, which are produced and released by microglia, have emerged as promising candidates to mediate interactions between microglia and synapses. The cellular effects of purines are mediated through a large family of receptors for adenosine and for ATP (P2 receptors)...
May 2016: European Journal of Neuroscience
Adam Wright, Martyn Mahaut-Smith, Fiona Symon, Nicolas Sylvius, Shaun Ran, Mona Bafadhel, Michelle Muessel, Peter Bradding, Andrew Wardlaw, Catherine Vial
Eosinophils play an important role in the pathogenesis of asthma and can be activated by extracellular nucleotides released following cell damage or inflammation. For example, increased ATP concentrations were reported in bronchoalveolar lavage fluids of asthmatic patients. Although eosinophils are known to express several subtypes of P2 receptors for extracellular nucleotides, their function and contribution to asthma remain unclear. In this article, we show that transcripts for P2X1, P2X4, and P2X5 receptors were expressed in healthy and asthmatic eosinophils...
June 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Tomohiko Ozaki, Rieko Muramatsu, Miwa Sasai, Masahiro Yamamoto, Yoshiaki Kubota, Toshiyuki Fujinaka, Toshiki Yoshimine, Toshihide Yamashita
Ischemic preconditioning (IPC), a procedure consisting of transient ischemia and subsequent reperfusion, provides ischemic tolerance against prolonged ischemia in the brain. Although the blood flow changes mediated by IPC are primarily perceived by vascular endothelial cells, the role of these cells in ischemic tolerance has not been fully clarified. In this study, we found that the P2X4 receptor, which is abundantly expressed in vascular endothelial cells, is required for ischemic tolerance following middle artery occlusion (MCAO) in mice...
2016: Scientific Reports
Shuo Li, Xiaoli Chen, Gaixiang Hao, Xuyun Geng, Wenbin Zhan, Jinsheng Sun
P2X2 receptor (P2X2R) belongs to the family of purinergic receptors that have been shown to play important roles in regulating host innate immune response. Although the immunologic significance of P2X2R has been studied in mammals, the presence and immune relevance of P2X2R in fish remains unclear. In this study we extended our previous observations by identifying and characterizing a P2X2R ortholog (termed PoP2X2R) from Japanese flounder (Paralichthys olivaceus). Quantitative real-time PCR analysis revealed that PoP2X2R mRNA transcripts are widely distributed in all examined normal tissues and are dominantly expressed in hepatopancreas tissue...
July 2016: Fish & Shellfish Immunology
Eric Pollatzek, Norma Hitzel, Daniela Ott, Katrin Raisl, Bärbel Reuter, Rüdiger Gerstberger
The arcuate nucleus (ARC) plays an important role in the hypothalamic control of energy homeostasis. Expression of various purinoceptor subtypes in the rat ARC and physiological studies suggest a modulatory function of P2 receptors within the neuroglial ARC circuitry. A differentiated mixed neuronal and glial microculture was therefore established from postnatal rat ARC, revealing neuronal expression of ARC-specific transmitters involved in food intake regulation (neuropeptide Y (NPY), proopiomelanocortin (POMC), tyrosine hydroxylase (TH))...
July 7, 2016: Neuroscience
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