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P2 Receptors

Yuichiro Fukumoto, Kenji F Tanaka, Bijay Parajuli, Keisuke Shibata, Hideyuki Yoshioka, Kazuya Kanemaru, Christian Gachet, Kazuhiro Ikenaka, Schuichi Koizumi, Hiroyuki Kinouchi
Extracellular ATP, which is released from damaged cells after ischemia, activates P2 receptors. P2Y1 receptors (P2Y1 R) have received considerable attention, especially in astrocytes, because their activation plays a central role in the regulation of neuron-to-glia communication. However, the functions or even existence of P2Y1 R in microglia remain unknown, despite the fact that many microglial P2 receptors are involved in several brain diseases. Herein, we demonstrate the presence and functional capability of microglial P2Y1 R to provide neuroprotective effects following ischemic stress...
October 18, 2018: Journal of Cerebral Blood Flow and Metabolism
Piotr Sirko, Jonathan E Gale, Jonathan F Ashmore
Intercellular Ca2+ waves are increases in cytoplasmic Ca2+ levels that propagate between cells Periodic Ca2+ waves have been linked to gene regulation and are thought to play a crucial role in the development of our hearing epithelium the organ of Corti and the acquisition of hearing We have observed regular periodic intercellular Ca2+ waves in supporting cells of an ex vivo preparation of the adult mouse organ of Corti, the waves were found to propagate independently of extracellular ATP and were inhibited by the gap junction blockers 1-octanol and carbenoxolone...
October 15, 2018: Journal of Physiology
Ramin Lotfi, Lena Steppe, Regina Hang, Markus Rojewski, Marina Massold, Bernd Jahrsdörfer, Hubert Schrezenmeier
INTRODUCTION: MSCs are often found within tumors, promote cancer progression and enhance metastasis. MSCs can act as immuosuppressive cells, partially due to the expression of the enzyme indoleamine dioxygenase (IDO) which converts tryptophan to kynurenine. Decreased concentration of tryptophan and increased kynurenine, both interfere with effective immune response. Damage associated molecular patterns (DAMPs) including ATP are found within the tumor microenvironment, attract MSCs, and influence their biology...
October 10, 2018: Immunity, Inflammation and Disease
Yung-Hui Kuan, Hsi-Chien Shih, Bai-Chuang Shyu
Central pain is commonly found in patients with neurological complications that are associated with central nervous system insult, such as stroke. It can result directly from central nervous system injury. Impairments in sensory discrimination can make it challenging to differentiate central neuropathic pain from other types of pain or spasticity. Central neuropathic pain may also begin months to years after the injury, further obscuring the recognition of its association with past neurologic injury. This chapter focuses on the involvement of P2 X7 receptor and brain-derived neurotrophic factor (BDNF) in central poststroke pain (CPSP)...
2018: Advances in Experimental Medicine and Biology
Taylor E T Hughes, Ruth A Pumroy, Aysenur Torun Yazici, Marina A Kasimova, Edwin C Fluck, Kevin W Huynh, Amrita Samanta, Sudheer K Molugu, Z Hong Zhou, Vincenzo Carnevale, Tibor Rohacs, Vera Y Moiseenkova-Bell
TRPV5 is a transient receptor potential channel involved in calcium reabsorption. Here we investigate the interaction of two endogenous modulators with TRPV5. Both phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2 ) and calmodulin (CaM) have been shown to directly bind to TRPV5 and activate or inactivate the channel, respectively. Using cryo-electron microscopy (cryo-EM), we determined TRPV5 structures in the presence of dioctanoyl PI(4,5)P2 and CaM. The PI(4,5)P2 structure reveals a binding site between the N-linker, S4-S5 linker and S6 helix of TRPV5...
October 10, 2018: Nature Communications
Michael Fine, Philip Schmiege, Xiaochun Li
Transient receptor potential mucolipin 1 (TRPML1), a lysosomal channel, maintains the low pH and calcium levels for lysosomal function. Several small molecules modulate TRPML1 activity. ML-SA1, a synthetic agonist, binds to the pore region and phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2 ), a natural lipid, stimulates channel activity to a lesser extent than ML-SA1; moreover, PtdIns(4,5)P2 , another natural lipid, prevents TRPML1-mediated calcium release. Notably, PtdIns(3,5)P2 and ML-SA1 cooperate further increasing calcium efflux...
October 10, 2018: Nature Communications
Tetyana Zhelay, Krystyna B Wieczerzak, Pavani Beesetty, Gerald M Alter, Masayuki Matsushita, J Ashot Kozak
Transient receptor potential cation channel subfamily M member 7 (TRPM7) is an ion channel/protein kinase belonging to the TRP melastatin and eEF2 kinase families.  Under physiological conditions, most native TRPM7 channels are inhibited by cytoplasmic Mg2+ , protons and polyamines.  Currents through these channels (ITRPM7 ) are robustly potentiated when the cell interior is exchanged with low Mg2+ -containing buffers.  ITRPM7 is also potentiated by phosphatidyl inositol bisphosphate (PI(4,5)P2 ) and suppressed by its hydrolysis...
October 10, 2018: Journal of Biological Chemistry
Naiara Stefanello, Roselia Spanevello, Sabina Passamonti, Lisiane Porciúncula, Carla Denise Bonan, Ayodeji Augustine Olabiyi, João Batista Teixeira da Rocha, Charles Elias Assmann, Vera Maria Morsch, Maria Rosa Chitolina Schetinger
Coffee is a drink prepared from roasted coffee beans and is lauded for its aroma and flavour. It is the third most popular beverage in the world. This beverage is known by its stimulant effect associated with the presence of metylxantines. Caffeine, a purine-like compound (1,3,7 trymetylxantine), is the most important bioactive compound in coffee, among other compounds such as chlorogenic acid (CGA), diterpenes, and trigonelline. Chlorogenic acid is a phenolic acid with biological proprieties described as an antioxidant, anti-inflammatory, neuroprotector, hipolipidemic, and hipoglicemic compound...
October 3, 2018: Food and Chemical Toxicology
Jie Gao, Wenwen Xin, Jing Huang, Bin Ji, Shan Gao, Liang Chen, Lin Kang, Hao Yang, Xin Shen, Baohua Zhao, Jinglin Wang
Epsilon-toxin (ETX) is produced by types B and D strains of Clostridium perfringens, which cause fatal enterotoxaemia in sheep, goats and cattle. Previous studies showed that only a restricted number of cell lines are sensitive to ETX and ETX-induced hemolysis has not previously been reported. In this study, the hemolytic ability of ETX was examined using erythrocytes from 10 species including murine, rabbit, sheep, monkey and human. We found that ETX caused hemolysis in human erythrocytes (HC50 =0.2 μM) but not erythrocytes from the other test species...
October 2, 2018: Virulence
Hai-Feng Lu, Chun-Yang Xu, Lei Zhang, Lei Gan, Chan Chen, Man-Yun Yan, Xiao-Ning Guo, Qi Fang, Guang-Yin Xu, Yan-Bo Zhang, Jian-Qiang Ni, Hong-Ru Zhao
Stroke is the leading cause of disability and death in the world. Central post-stroke pain (CPSP), a central neuropathic pain syndrome occurring after cerebral stroke, is a serious problem. But on account of the lack of reliable animal models, the mechanisms underlying CPSP remains poorly understood. To better understand of the pathophysiological basis of CPSP, we developed and characterized a new rat model of CPSP. This model is based on a hemorrhagic stroke lesion with intra-thalamic autologous blood (ITAB) injection in the ventral posterolateral nucleus of the thalamus...
September 26, 2018: Neuroscience Letters
Kung-Chieh Wu, Bing-Juin Chiang, Wen-Hsin Tsai, Shiu-Dong Chung, Chiang-Ting Chien
AIMS: We explored the therapeutic potential of intragastric administration traditional Chinese medicine Glycine tomentella Hayata (I-Tiao-Gung, ITG) extract and its active component Daidzin on cyclophosphamide (CYP)-induced cystitis and bladder hyperactivity in rats. METHODS: Female Wistar rats were divided into control, CYP (200 mg/kg), CYP + ITG (1.17 g/kg/day), CYP + Daidzin (12.5 mg/kg/day), and 1 week of ITG preconditioning with CYP (ITG + CYP) groups...
September 3, 2018: Neurourology and Urodynamics
Albert H Lee, Carola Ledderose, Xiaoou Li, Christian J Slubowski, Koichiro Sueyoshi, Laura Staudenmaier, Yi Bao, Jingping Zhang, Wolfgang G Junger
OBJECTIVES: Monocytes and macrophages produce interleukin-1β by inflammasome activation which involves adenosine triphosphate release, pannexin-1 channels, and P2X7 receptors. However, interleukin-1β can also be produced in an inflammasome-independent fashion. Here we studied if this mechanism also involves adenosine triphosphate signaling and how it contributes to inflammasome activation. DESIGN: In vitro studies with human cells and randomized animal experiments...
September 20, 2018: Critical Care Medicine
Eliandra N da Silva, José de Anchieta C Horta-Júnior, Luciane H Gargaglioni, Mirela B Dias
NEW FINDINGS: What is the central question of this study? ATP is known to modulate the chemosensitivity of some brain areas. However, whether the ATP contributes specifically to the mechanism of chemoreception in the lateral hypothalamus/perifornical area (LH/PFA) remains to be determined. What is the main finding and its importance? ATP, acting on the LH/PFA, enhances the hypercapnic ventilatory response in rats during wakefulness, in the dark period. Our results highlight the importance of ATP as a modulator of central chemoreception and provide new insight regarding the mechanisms involved in LH/PFA chemosensitivity and the sleep-wake differences in the CO2 /H+ -dependent drive to breathe...
September 22, 2018: Experimental Physiology
Chérifi Fatah, Saoud Samah, Laraba-Djebari Fatima
This study aimed to elucidate anticoagulant/antiplatelet mechanisms of two previously purified PLA2 s from Cerastes cerastes venom, here, termed Cc1 -PLA2 and Cc2 -PLA2 . Both PLA2 s present close molecular weights of 13,534 and 13,430 Da and Isoectric pH (pI) 7.38 and 7.86 respectively, for Cc1 -PLA2 and Cc2 -PLA2 . These Ca2+ -dependent enzymes showed a high catalytic activity upon phospholipids, inducing indirect hemolysis, since they conserve the catalytic domain of PLA2 s 26 CYCGWGGKG34 . They exhibited dual inhibition of platelet aggregation by targeting P2 Y12 and TPα receptors preventing Adenosine diphosphate/arachidonate binding and blood clotting...
September 21, 2018: Journal of Biochemical and Molecular Toxicology
Di Du, Zhibin Zhou, Lei Zhu, Xianteng Hu, Jiajia Lu, Changgui Shi, Fangjing Chen, Aimin Chen
Tumor Necrosis Factor-α (TNF-α)-inhibited osteogenic differentiation of mesenchymal stem cells (MSCs) contributes to impaired bone formation, which plays a central role in the pathogenesis of postmenopausal osteoporosis. However, the exact mechanisms of TNF-α-inhibited osteoblast differentiation have not been fully elucidated. Multiple P2 purinoceptor subtypes are expressed in several species of osteoblasts and are confirmed to regulate bone metabolism. The purpose of this study is to investigate whether P2 purinoceptors are involved in TNF-α-inhibited osteoblast differentiation...
September 17, 2018: Bone
Christian M Gawden-Bone, Gordon L Frazer, Arianne C Richard, Claire Y Ma, Katharina Strege, Gillian M Griffiths
How cytotoxic T lymphocytes (CTLs) sense T cell receptor (TCR) signaling in order to specialize an area of plasma membrane for granule secretion is not understood. Here, we demonstrate that immune synapse formation led to rapid localized changes in the phosphoinositide composition of the plasma membrane, both reducing phosphoinositide-4-phosphate (PI(4)P), PI(4,5)P2, and PI(3,4,5)P3 and increasing diacylglycerol (DAG) and PI(3,4)P2 within the first 2 min of synapse formation. These changes reduced negative charge across the synapse, triggering the release of electrostatically bound PIP5 kinases that are required to replenish PI(4,5)P2...
September 18, 2018: Immunity
Eliane Berrou, Christelle Soukaseum, Rémi Favier, Frédéric Adam, Ziane Elaib, Alexandre Kauskot, Jean-Claude Bordet, Paola Ballerini, Stephane Loyau, Miao Feng, Karine Dias, Abbas Muheidli, Stephane Girault, Alan T Nurden, Ernest Turro, Willem H Ouwehand, Cécile V Denis, Martine Jandrot-Perrus, Jean-Philippe Rosa, Paquita Nurden, Marijke Bryckaert
The ephrin transmembrane receptor (EPHR) family of tyrosine kinases is involved in platelet function. We report the first EPHB2 variant affecting platelets in two siblings (P1 and P2) from a consanguineous family with recurrent bleeding and normal platelet counts. Whole exome sequencing identified a c.2233C>T variant (missense p.R745C) of the EPHB2 gene. P1 and P2 were homozygous for this variant while their asymptomatic parents were heterozygous. The p.R745C variant within the tyrosine kinase domain was associated with defects in platelet aggregation, αIIbβ3 activation and granule secretion induced by GPCR (G protein-coupled receptors) agonists and convulxin as well as in thrombus formation on collagen under flow...
September 13, 2018: Blood
Maki Sato, Tadasu Sato, Takehiro Yajima, Kenichiro Shimazaki, Hiroyuki Ichikawa
OBJECTIVE: Distribution of the transient receptor potential cation channel subfamily V members 1 (TRPV1) and 2 (TRPV2), and P2X purinoceptor 3 (P2 × 3) was investigated in rat trigeminal ganglion neurons innervating the periosteum, masseter muscle and facial skin. DESIGN: Double immunofluorescence method for TRPV1 and TRPV2 ion channels or ATP receptor P2 × 3 with calcitonin gene-related peptide (CGRP) was performed on trigeminal ganglion neurons retrogradely labeled from the mandibular periosteum, masseter muscle, or facial skin in 15 male Wistar rats...
August 30, 2018: Archives of Oral Biology
Christopher A Nelson, Craig B Wilen, Ya-Nan Dai, Robert C Orchard, Arthur S Kim, Roderick A Stegeman, Leon L Hsieh, Thomas J Smith, Herbert W Virgin, Daved H Fremont
Murine norovirus (MNoV) is closely related to human norovirus (HNoV), an infectious agent responsible for acute gastroenteritis worldwide. Here we report the X-ray crystal structure of the dimeric MNoV VP1 protruding (P) domain in complex with its cellular receptor CD300lf. CD300lf binds the P domain with a 2:2 stoichiometry, engaging a cleft between the AB and DE loops of the P2 subdomain at a site that overlaps the epitopes of neutralizing antibodies. We also identify that bile acids are cofactors enhancing MNoV cell-binding and infectivity...
September 25, 2018: Proceedings of the National Academy of Sciences of the United States of America
Shangdong Guo, Hong Lu
Hepatocyte nuclear factor 4α (HNF4α) is a master regulator of development and function of digestive tissues. The HNF4A gene uses two separate promoters P1 and P2, with P1 products predominant in adult liver, whereas P2 products prevalent in fetal liver, pancreas, and liver/colon cancer. To date, the mechanisms for the regulation of HNF4A and the dynamic switch of P1-HNF4α and P2-HNF4α during ontogenesis and carcinogenesis are still obscure. Our study validated the previously reported self-stimulation of P1-HNF4α but invalidated the reported synergism between HNF4α and HNF1α...
September 7, 2018: Journal of Cellular Biochemistry
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