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P2Y4 and heart

Ulrich Gergs, Daniel Rothkirch, Britt Hofmann, Hendrik Treede, Bernard Robaye, Andreas Simm, Christa E Müller, Joachim Neumann
We previously reported that uridine 5'-triphosphate (UTP), a pyrimidine nucleoside triphosphate produced a concentration- and time-dependent increase in the contraction force in isolated right atrial preparations from patients undergoing cardiac bypass surgery due to angina pectoris. The stimulation of the force of contraction was sustained rather than transient. In the present study, we tried to elucidate the underlying receptor and signal transduction for this effect of UTP. Therefore, we measured the effect of UTP on force of contraction, phosphorylation of p38 and ERK1/2, in human atrial preparations, atrial preparations from genetically modified mice, cardiomyocytes from adult mice and cardiomyocytes from neonatal rats...
July 5, 2018: European Journal of Pharmacology
Muhammad Rafehi, Enas M Malik, Alexander Neumann, Aliaa Abdelrahman, Theodor Hanck, Vigneshwaran Namasivayam, Christa E Müller, Younis Baqi
P2Y4 is a Gq protein-coupled receptor activated by uridine-5'-triphosphate (UTP), which is widely expressed in the body, e.g., in intestine, heart, and brain. No selective P2Y4 receptor antagonist has been described so far. Therefore, we developed and optimized P2Y4 receptor antagonists based on an anthraquinone scaffold. Potency was assessed by a fluorescence-based assay measuring inhibition of UTP-induced intracellular calcium release in 1321N1 astrocytoma cells stably transfected with the human P2Y4 receptor...
April 13, 2017: Journal of Medicinal Chemistry
Mariana Certal, Adriana Vinhas, Aurora Barros-Barbosa, Fátima Ferreirinha, Maria Adelina Costa, Paulo Correia-de-Sá
Nucleotides released during heart injury affect myocardium electrophysiology and remodeling through P2 purinoceptors activation in cardiac myofibroblasts. ATP and UTP endorse [Ca(2+) ]i accumulation and growth of DDR-2/α-SMA-expressing myofibroblasts from adult rat ventricles via P2Y4 and P2Y2 receptors activation, respectively. Ventricular myofibroblasts also express ADP-sensitive P2Y1 , P2Y12 , and P2Y13 receptors as demonstrated by immunofluorescence confocal microscopy and western blot analysis, but little information exists on ADP effects in these cells...
June 2017: Journal of Cellular Physiology
Sophie Clouet, Larissa Di Pietrantonio, Evangelos-Panagiotis Daskalopoulos, Hrag Esfahani, Michael Horckmans, Marion Vanorlé, Anne Lemaire, Jean-Luc Balligand, Christophe Beauloye, Jean-Marie Boeynaems, Didier Communi
The study of the mechanisms leading to cardiac hypertrophy is essential to better understand cardiac development and regeneration. Pathological conditions such as ischemia or pressure overload can induce a release of extracellular nucleotides within the heart. We recently investigated the potential role of nucleotide P2Y receptors in cardiac development. We showed that adult P2Y4-null mice displayed microcardia resulting from defective cardiac angiogenesis. Here we show that loss of another P2Y subtype called P2Y6, a UDP receptor, was associated with a macrocardia phenotype and amplified pathological cardiac hypertrophy...
July 22, 2016: Journal of Biological Chemistry
Safoura Mazrouei, Fatemeh Sharifpanah, Mohamed M Bekhite, Hans-Reiner Figulla, Heinrich Sauer, Maria Wartenberg
Purinergic signaling may be involved in embryonic development of the heart. In the present study, the effects of purinergic receptor stimulation on cardiomyogenesis of mouse embryonic stem (ES) cells were investigated. ADP or ATP increased the number of cardiac clusters and cardiac cells, as well as beating frequency. Cardiac-specific genes showed enhanced expression of α-MHC, MLC2v, α-actinin, connexin 45 (Cx45), and HCN4, on both gene and protein levels upon ADP/ATP treatment, indicating increased cardiomyogenesis and pacemaker cell differentiation...
December 2015: Purinergic Signalling
Mariana Certal, Adriana Vinhas, Ana Rita Pinheiro, Fátima Ferreirinha, Aurora Raquel Barros-Barbosa, Isabel Silva, Maria Adelina Costa, Paulo Correia-de-Sá
During myocardial ischemia and reperfusion both purines and pyrimidines are released into the extracellular milieu, thus creating a signaling wave that propagates to neighboring cells via membrane-bound P2 purinoceptors activation. Cardiac fibroblasts (CF) are important players in heart remodeling, electrophysiological changes and hemodynamic alterations following myocardial infarction. Here, we investigated the role UTP on calcium signaling and proliferation of CF cultured from ventricles of adult rats. Co-expression of discoidin domain receptor 2 and α-smooth muscle actin indicate that cultured CF are activated myofibroblasts...
November 2015: Cell Calcium
Michael Horckmans, Hrag Esfahani, Christophe Beauloye, Sophie Clouet, Larissa di Pietrantonio, Bernard Robaye, Jean-Luc Balligand, Jean-Marie Boeynaems, Chantal Dessy, Didier Communi
Nucleotides are released in the heart under pathological conditions, but little is known about their contribution to cardiac inflammation. The present study defines the P2Y4 nucleotide receptor, expressed on cardiac microvascular endothelial cells and involved in postnatal heart development, as an important regulator of the inflammatory response to cardiac ischemia. P2Y4-null mice displayed smaller infarcts in the left descending artery ligation model, as well as reduced neutrophil infiltration and fibrosis...
February 15, 2015: Journal of Immunology
Kwok-Kuen Cheung, Camila Marques-da-Silva, Leandro Vairo, Danúbia Silva dos Santos, Regina Goldenberg, Robson Coutinho-Silva, Geoffrey Burnstock
Purinergic receptors activated by extracellular nucleotides (adenosine 5'-triphosphate (ATP) and uridine 5'-triphosphate (UTP)) are well known to exert physiological effects on the cardiovascular system, whether nucleotides participate functionally in embryonic heart development is not clear. The responsiveness of embryonic cardiomyocytes (E) 12 to P2 receptor agonists by measuring Ca(2+) influx did not present response to ATP, but responses to P2 agonists were detected in cardiomyocytes taken from E14 and E18 rats...
March 2015: Purinergic Signalling
Ulrich Gergs, Andreas Simm, Hasan Bushnaq, Rolf-Edgar Silber, Joachim Neumann
In the cardio-vascular system extracellular UTP can induce receptor-mediated vasoconstriction via smooth muscle cells and vasodilatation via endothelial cells. We evaluated inotropic effects of UTP in preparations from human heart. Contractile effects were studied in atrial preparations from patients undergoing cardiac bypass surgery. For comparison, contractility in isolated spontaneously beating right atrial and paced left atrial preparations from mice was investigated. UTP and UTPγS concentration-dependently exerted a positive inotropic effect with a maximum at 100 µM UTP that amounted to 156% of pre-drug value (n=13) without changing time parameters of contraction...
February 5, 2014: European Journal of Pharmacology
Edith Hochhauser, Ronit Cohen, Maayan Waldman, Anna Maksin, Ahuva Isak, Dan Aravot, P Suresh Jayasekara, Christa E Müller, Kenneth A Jacobson, Asher Shainberg
Extracellular nucleotides acting via P2 receptors play important roles in cardiovascular physiology/pathophysiology. Pyrimidine nucleotides activate four G protein-coupled P2Y receptors (P2YRs): P2Y2 and P2Y4 (UTP-activated), P2Y6, and P2Y14. Previously, we showed that uridine 5'-triphosphate (UTP) activating P2Y2R reduced infarct size and improved mouse heart function after myocardial infarct (MI). Here, we examined the cardioprotective role of P2Y2R in vitro and in vivo following MI using uridine-5'-tetraphosphate δ-phenyl ester tetrasodium salt (MRS2768), a selective and more stable P2Y2R agonist...
December 2013: Purinergic Signalling
Joseph E Brayden, Yao Li, Matthew J Tavares
Myogenic tone is a fundamental aspect of vascular behavior in resistance arteries. This contractile response to changes in intravascular pressure is critically involved in blood flow autoregulation in tissues such as the brain, kidneys, and heart. Myogenic tone also helps regulate precapillary pressure and provides a level of background tone upon which vasodilator stimuli act to increase tissue perfusion when appropriate. Despite the importance of these processes in the brain, little is known about the mechanisms involved in control of myogenic tone in the cerebral microcirculation...
February 2013: Journal of Cerebral Blood Flow and Metabolism
Michael Horckmans, Elvira Léon-Gómez, Bernard Robaye, Jean-Luc Balligand, Jean-Marie Boeynaems, Chantal Dessy, Didier Communi
Nucleotides released within the heart under pathological conditions can be involved in cardioprotection or cardiac fibrosis through the activation purinergic P2Y(2) and P2Y(6) receptors, respectively. We previously demonstrated that adult P2Y(4)-null mice display a microcardia phenotype related to a cardiac angiogenic defect. To evaluate the functional consequences of this defect, we performed here a combination of cardiac monitoring and exercise tests. We investigated the exercise capacity of P2Y(4) wild-type and P2Y(4)-null mice in forced swimming and running tests...
October 1, 2012: American Journal of Physiology. Heart and Circulatory Physiology
Ivar von Kügelgen
Membrane-bound P2-receptors mediate the actions of extracellular nucleotides in cell-to-cell signalling. P2X-receptors are ligand-gated ion channels, whereas P2Y-receptors belong to the superfamily of G-protein-coupled receptors (GPCRs). So far, the P2Y family is composed out of 8 human subtypes that have been cloned and functionally defined; species orthologues have been found in many vertebrates. P2Y1-, P2Y2-, P2Y4-, P2Y6-, and P2Y11-receptors all couple to stimulation of phospholipase C. The P2Y11-receptor mediates in addition a stimulation of adenylate cyclase...
June 2006: Pharmacology & Therapeutics
Smadar Yitzhaki, Vladimir Shneyvays, Kenneth A Jacobson, Asher Shainberg
Cardiomyocytes express one or more subtypes of P2 receptors for extracellular nucleotides. P2 purinoceptors, which are activated by nucleotides, are classified as P2X or P2Y: P2X receptors are ligand-gated intrinsic ion channels, and P2Y receptors are G protein-coupled receptors. Extracellular pyrimidine and purine nucleotides are released from the heart during hypoxia. Although the cardioprotective effects of purines acting via purinoceptors were studied intensively, the physiological role of uracil nucleotide-responsive P2Y2, P2Y4, P2Y6, and P2Y14 receptors is still unclear, especially in the cardiovascular system...
April 15, 2005: Biochemical Pharmacology
Kwok-Kuen Cheung, Mina Ryten, Geoffrey Burnstock
Extracellular ATP mediates diverse biological effects by activating two families of receptors, the P2X and P2Y receptors. There is growing evidence to show that activation of G protein-coupled P2Y receptors can produce trophic effects in many cell types. Yet the expression and function of the P2Y receptors in development has rarely been studied and has never been investigated in mammalian development. This study used the reverse transcription-polymerase chain reaction and immunohistochemistry to demonstrate the abundant and dynamic expression of P2Y receptors in rat development...
October 2003: Developmental Dynamics
I von Kügelgen, A Wetter
Membrane-bound P2-receptors mediate the actions of extracellular nucleotides in cell-to-cell signalling. P2X-receptors are ligand-gated ion channels, whereas P2Y-receptors belong to the superfamily of G-protein-coupled receptors. So far, the P2Y family is composed of eight cloned and functionally defined subtypes. Five of them (P2Y1, P2Y2, P2Y4, P2Y6 and P2Y11) are present in human tissues. The P2Y3-, p2y8- and tp2y-receptors may be species orthologues. The principal physiological agonists of the cloned human P2Y-receptors are ADP (P2Y1), UTP/ATP (P2Y2), UTP (P2Y4), UDP (P2Y6) and ATP (P2Y11)...
November 2000: Naunyn-Schmiedeberg's Archives of Pharmacology
D M Liu, C Katnik, M Stafford, D J Adams
1. The mobilization of Ca2+ by purinoceptor activation and the relative contributions of intra- and extracellular sources of Ca2+ were investigated using microfluorimetric measurements of fura-2 loaded in cultured neurones from rat intracardiac ganglia. 2. Reverse transcriptase-polymerase chain reaction (RT-PCR) revealed expression of mRNA for the G protein-coupled P2Y2 and P2Y4 receptors. 3. Brief application of either 300 microM ATP or 300 microM UTP caused transient increases in [Ca2+]i of 277 +/- 22 nM and 267 +/- 39 nM, respectively...
July 15, 2000: Journal of Physiology
M Hou, M Malmsjö, S Möller, E Pantev, A Bergdahl, X H Zhao, X Y Sun, T Hedner, L Edvinsson, D Erlinge
We wanted to study the expression of P2-receptors at the mRNA-level in the heart and if it is affected by congestive heart failure (CHF). To quantify the P2 receptor mRNA-expression we used a competitive RT-PCR protocol which is based on an internal RNA standard. The P2 receptor mRNA-expression was quantified in hearts from CHF rats and compared to sham-operated rats. Furthermore, the presence of receptor mRNA was studied in the myocardium from patients with heart failure. In the sham operated rats the G-protein coupled P2Y-receptors were expressed at a higher level than the ligand gated ion-channel receptor (P2X1)...
1999: Life Sciences
Y D Bogdanov, S S Wildman, M P Clements, B F King, G Burnstock
An intronless open reading frame encoding a protein (361aa in length) was isolated from a rat genomic library probed with a DNA fragment from rat heart. This protein showed 83% sequence identity with the human P2Y4 (hP2Y4) receptor and represents a homologue of the human pyrimidinoceptor. However, the rP2Y4 receptor is not selective for uridine nucleotides and, instead, shows an agonist potency order of ITP = ATP = ADP(pure) = UTP = ATPgammaS = 2-MeSATP = Ap4A > UDP(pure). ADP, ATPgammaS, 2-MeSATP and UDP are partial agonists...
June 1998: British Journal of Pharmacology
Y Bogdanov, A Rubino, G Burnstock
ATP exerts a variety of actions within the myocardium, including the regulation of coronary vascular tone and modulation of the autonomic control of the heart. In order to characterise the ATP receptor subtypes involved in these effects, degenerate oligonucleotides were used to clone receptors of both P2X and P2Y families from the human foetal heart. About 1 ng of "Quick-Clone cDNA" from foetal human heart was subjected to amplification with two pairs of degenerate oligonucleotides designed to amplify subtypes of the P2X and P2Y receptor families by means of PCR reactions...
1998: Life Sciences
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