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Miho Sugioka, Yasuhiko Saito
In the nervous system, adenosine 5'-trisphosphate (ATP) functions as a neurotransmitter and binds to ionotropic P2X receptors and metabotropic P2Y receptors. Although ATP receptors are expressed in the prepositus hypoglossi nucleus (PHN), which is a brainstem structure involved in controlling horizontal gaze, it is unclear whether ATP indeed affects the activity of PHN neurons. In this study, we investigated the effects of ATP on spontaneous firing of PHN neurons using whole-cell recordings in rat brainstem slices...
October 19, 2018: European Journal of Neuroscience
Julian Merz, Philipp Albrecht, Sunaina von Garlen, Ibrahim Ahmed, Daniel Dimanski, Dennis Wolf, Ingo Hilgendorf, Carmen Härdtner, Katja Grotius, Florian Willecke, Timo Heidt, Heiko Bugger, Natalie Hoppe, Ulrich Kintscher, Constantin von Zur Mühlen, Marco Idzko, Christoph Bode, Andreas Zirlik, Peter Stachon
Sterile inflammation of visceral fat, provoked by dying adipocytes, links the metabolic syndrome to cardiovascular disease. Danger-associated molecular patterns, such as adenosine triphosphate (ATP), are released by activated or dying cells and orchestrate leukocyte infiltration and inflammation via the purinergic receptor P2Y2 . The gene expression of ATP receptor P2Y2 did not change in several tissues in the course of obesity, but was increased within epididymal fat. Adipose tissue from P2Y 2 -/- mice consuming high-fat diet (HFD) contained less crown-like structures with a reduced frequency of adipose tissue macrophages (ATMs)...
October 18, 2018: Basic Research in Cardiology
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
Seema B Ali, Jeremy J O Turner, Samuel J Fountain
White adipocytes are key regulators of metabolic homeostasis, which release stored energy as free fatty acids via lipolysis. Adipocytes possess both basal and stimulated lipolytic capacity, but limited information exists regarding the molecular mechanisms that regulate basal lipolysis. Here, we describe a mechanism whereby autocrine purinergic signaling and constitutive P2Y2 receptor activation suppresses basal lipolysis in primary human in vitro differentiated adipocytes. We found that human adipocytes possess cytoplasmic calcium tone due to ATP secretion and constitutive P2Y2 receptor activation...
October 17, 2018: Journal of Cell Science
Cai Liu, Yifan Zhang, Weili Chen, Youming Lu, Wei Li, Yongqiang Liu, Xiaojuan Lai, Yanchun Gong, Xuefang Liu, Yongguo Li, Xiaoyan Chen, Xuening Li, Hongbin Sun, Jin Yang, Dafang Zhong
BACKGROUND AND OBJECTIVES: Vicagrel, a novel thienopyridine antiplatelet agent, is an analogue of clopidogrel in development for the treatment of acute coronary syndromes. This study investigated the pharmacokinetic properties of vicagrel after single oral dosing with a direct comparison with clopidogrel in healthy Chinese subjects in the first two phase I clinical studies. The relationship between the exposure to the active metabolite and the platelet reactivity was also assessed for vicagrel...
October 13, 2018: European Journal of Pharmaceutical Sciences
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
Ying Gao, Cheng Yu, Shulan Pi, Ling Mao, Bo Hu
Atherosclerosis is a chronic and progressive disease of the arterial walls and a leading cause of non-cardioembolic ischemic stroke. P2Y12 is a well-recognized receptor that is expressed on platelets and is a target of thienopyridine-type antiplatelet drugs. In the last few decades, P2Y12 receptor inhibitors, such as clopidogrel, have been applied for the secondary prevention of non-cardioembolic ischemic stroke. Recent clinical studies have suggested that these P2Y12 receptor inhibitors may be more effective than other antiplatelet drugs in patients with ischemic stroke/transient ischemic attack of atherosclerotic origin...
October 9, 2018: Cellular and Molecular Life Sciences: CMLS
Younis Baqi, Christa E Müller
The P2Y12 receptor is one of eight known P2Y receptor subtypes, and belongs to the G-protein-coupled receptor (GPCR) family. The P2Y12 receptor is highly expressed on blood platelets and in the brain. Potent, selective, peripherally acting antagonists for the P2Y12 receptor are used clinically as antithrombotic drugs. Several different scaffolds have been identified as P2Y12 receptor antagonists, including irreversibly acting thienotetrahydropyridines (prodrugs), and reversible competitive antagonists, including adenine nucleotide analogs, piperazinyl-glutamate-quinolines, -pyridines, and -pyrimidines, and anthraquinone derivatives...
October 3, 2018: Drug Discovery Today
A L Frelinger, C Gachet, A D Mumford, P Noris, D Mezzano, P Harrison, P Gresele
No abstract text is available yet for this article.
September 4, 2018: Journal of Thrombosis and Haemostasis: JTH
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
Bin Liu, Wanxin Cao, Jiping Li, Jun Liu
Adenosine triphosphate (ATP) is stored as lysosomal vesicles in marginal cells of the stria vascular in neonatal rats, but the mechanisms of ATP release are unclear. Primary cultures of marginal cells from 1-day-old Sprague-Dawley rats were established. P2Y2 receptor and inositol 1,4,5-trisphosphate (IP3) receptor were immunolabelled in marginal cells of the stria vascular. We found that 30 μM ATP and 30 μM uridine triphosphate (UTP) evoked comparable significant increases in the intracellular Ca2+ concentration ([Ca2+ ]i ) in the absence of extracellular Ca2+ , whereas the response was suppressed by 100 μM suramin, 10 μM 1-(6-(17β-3-methoxyester-1,3,5(10)-trien-17-yl)amino)-hexyl)-1H-pyrrole-2,5-dione(U-73122), 100 μM 2-aminoethoxydiphenyl borate (2-APB) and 5 μM thapsigargin (TG), thus indicating that ATP coupled with the P2Y2 R-PLC-IP3 pathway to evoke Ca2+ release from the endoplasmic reticulum (ER)...
September 21, 2018: Cell Calcium
Martino Pepe, Alessandro Cafaro, Valeria Paradies, Nicola Signore, Francesco Addabbo, Alessandro Santo Bortone, Eliano Pio Navarese, Gaetano Contegiacomo, Cinzia Forleo, Francesco Bartolomucci, Ottavio Di Cillo, Francesco Paolo Bianchi, Domenico Zanna, Stefano Favale
OBJECTIVES: The aim of this observational study was to determine the benefits of the novel, orally delivered P2Y12 -inhibitors (Is) in terms of angiographic endpoints and in relation to the time of the loading dose (LD) administration. BACKGROUND: The goal of ST-elevation myocardial infarction (STEMI) treatment is timely reperfusion. The P2Y12 -Is prasugrel and ticagrelor have improved the angiographic outcome of primary percutaneous coronary intervention (pPCI) and patients' prognosis...
September 30, 2018: Catheterization and Cardiovascular Interventions
Elena Smolensky Koganov, Alan D Michelson, Ivan B Yanachkov, Milka I Yanachkova, George E Wright, Karin Przyklenk, Andrew L Frelinger
Dual antiplatelet therapy with aspirin and an adenosine diphosphate (ADP) P2Y12 receptor antagonist reduces ischemic events in patients with acute coronary syndrome. Previous evidence from our group, obtained in a preclinical model of recurrent platelet-mediated thrombosis, demonstrated that GLS-409, a diadenosine tetraphosphate derivative that inhibits both P2Y1 and P2Y12 ADP receptors, may be a novel and promising antiplatelet drug candidate. However, the salutary antiplatelet effects of GLS-409 were accompanied by a trend toward an unfavorable increase in bleeding...
September 28, 2018: Scientific Reports
Y Zhang, K M Hansson, T Liu, K Magnell, Y Huang, N G Carlson, B K Kishore
AIM: Therapeutic use of lithium in bipolar disorder is limited by the development of nephrogenic diabetes insipidus (NDI). We reported that pharmacological blockade of P2Y12 receptor (R) with clopidogrel or prasugrel significantly ameliorated lithium-induced NDI in rodents. Using mice genetically lacking P2Y12 -R we evaluated whether the observed amelioration is mediated through P2Y12 -R. METHODS: P2ry12-/- mouse line (C57/BL6) was rederived from cryopreserved embryos of the knockout (KO) mice generated by Deltagen Inc...
September 26, 2018: Acta Physiologica
Danny Kupka, Dirk Sibbing
Dual antiplatelet therapy (DAPT) - a combination of a P2Y₁₂ receptor inhibitor and aspirin - has revolutionized antithrombotic treatment. Potent P2Y₁₂ inhibitors such as prasugrel and ticagrelor exhibit a strong and more consistent platelet inhibition when compared to clopidogrel. Therefore, ticagrelor and prasugrel significantly reduce ischemic events, but at an expense of an increased bleeding risk in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). These observations have engaged intensive clinical research in alternative DAPT regimens to achieve sufficient platelet inhibition with an acceptable bleeding risk...
October 2018: Korean Circulation Journal
Tetsuto Nakagawa, Chihiro Takahashi, Hitomi Matsuzaki, Yoshiyuki Kuroda, Hideyoshi Higashi
Several G protein-coupled receptors are present in lipid rafts. We have shown that most of the P2Y2 receptor (P2Y2 R) protein is fractionated into lipid rafts in COS 7 cells. In the same cells, about 25-30% of the bradykinin B2 receptor (B2R) protein is also fractionated into lipid rafts. When both P2Y2 R and B2R are co-expressed, the distribution of P2Y2 R remained unchanged, but more B2R shifted into the raft fraction. This indicates that the interaction between both receptors recruited B2R into the lipid rafts...
September 17, 2018: Biochemical and Biophysical Research Communications
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
Naoki Ito, Urs T Ruegg, Shin'ichi Takeda
Intracellular signaling pathways, including the mammalian target of rapamycin (mTOR) and the mitogen-activated protein kinase (MAPK) pathway, are activated by exercise, and promote skeletal muscle hypertrophy. However, the mechanisms by which these pathways are activated by physiological stimulation are not fully understood. Here we show that extracellular ATP activates these pathways by increasing intracellular Ca2+ levels ([Ca2+ ]i ), and promotes muscle hypertrophy. [Ca2+ ]i in skeletal muscle was transiently increased after exercise...
September 18, 2018: International Journal of Molecular Sciences
Cita Bauer, Julia Kaiser, Jelena Sikimic, Peter Krippeit-Drews, Martina Düfer, Gisela Drews
PURPOSE: The role of ATP, which is secreted by pancreatic β-cells, is still a matter of debate. It has been postulated that extracellular ATP acts as a positive auto- or paracrine signal in β-cells amplifying insulin secretion. However, there is rising evidence that extracellular ATP may also mediate a negative signal. METHODS: We evaluated whether extracellular ATP interferes with the Ca2+ -mediated negative feedback mechanism that regulates oscillatory activity of β-cells...
September 18, 2018: Endocrine
Bing Zhao, Hao Wang, Cai-Xia Li, Sheng-Wen Song, San-Hua Fang, Er-Qing Wei, Qiao-Juan Shi
GPR17 is a G (i)-coupled dual receptor, linked to P2Y and CysLT receptors stimulated by uracil nucleotides and cysteinyl leukotrienes, respectively. Recent evidence has demonstrated that GPR17 inhibition ameliorates the progression of cerebral ischemic injury by regulating neuronal death and microglial activation. The present study aimed to assess the detailed regulatory roles of this receptor in oxygen‑glucose deprivation/recovery (OGD/R)‑induced ischemia‑like injury in vitro and explore the underlying mechanism...
November 2018: International Journal of Molecular Medicine
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