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Purinergic signalling

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https://www.readbyqxmd.com/read/28735873/the-therapeutic-potential-of-purinergic-signalling
#1
REVIEW
Geoffrey Burnstock
This review is focused on the pathophysiology and therapeutic potential of purinergic signalling. A wide range of diseases are considered, including those of the central nervous system, skin, kidney, musculoskeletal, liver gut, lower urinary tract, cardiovascular, airways and reproductive systems, the special senses, infection, diabetes and obesity. Several purinergic drugs are already on the market, including P2Y12 receptor antagonists for stroke and thrombosis, P2Y2 receptor agonists for dry eye, A1 receptor agonists for supraventricular tachycardia...
July 20, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28734869/p2x-receptors-up-regulate-the-cell-surface-expression-of-the-neuronal-glycine-transporter-glyt2
#2
Lucía Villarejo-López, Esperanza Jiménez, David Bartolomé-Martín, Francisco Zafra, Pablo Lapunzina, Carmen Aragón, Beatriz López-Corcuera
Glycinergic inhibitory neurons of the spinal dorsal horn exert critical control over the conduction of nociceptive signals to higher brain areas. The neuronal glycine transporter 2 (GlyT2) is involved in the recycling of synaptic glycine from the inhibitory synaptic cleft and its activity modulates intra and extracellular glycine concentrations. In this report we show that the stimulation of P2X purinergic receptors with βγ-methylene adenosine 5'-triphosphate induces the up-regulation of GlyT2 transport activity by increasing total and plasma membrane expression and reducing transporter ubiquitination...
July 19, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28729619/effects-of-4-1h-quinolinone-derivative-a-novel-non-nucleotide-allosteric-purinergic-p2y-2-agonist-on-cardiomyocytes-in-neonatal-rats
#3
Kensuke Sakuma, Hideyuki Nakagawa, Tatsuo Oikawa, Masakuni Noda, Shota Ikeda
Purinergic P2Y 2 receptors, G-protein coupled receptors that primarily couple with Gαq/11-proteins, are activated equipotently by adenosine-5'-triphosphate (ATP) and uridine-5'-triphosphate. Evidence suggests that P2Y 2 agonists make potential drug candidates for the treatment of cardiovascular diseases. However, selective non-nucleotide, small-molecule P2Y 2 agonists have yet to be developed. In this report, we discuss Compound 89, a novel non-nucleotide allosteric P2Y 2 agonist that was active in signal transduction and gene induction, and in our in vitro cardiac hypertrophy model...
July 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28729424/molecular-determinants-of-acidic-ph-dependent-transport-of-human-equilibrative-nucleoside-transporter-3
#4
Md Fazlur Rahman, Candice Askwith, Rajgopal Govindarajan
Equilibrative nucleoside transporters (ENTs) translocate hydrophilic nucleosides across cellular membranes and are essential for salvage nucleotide synthesis and purinergic signaling. Unlike the prototypic human ENT members hENT1 and hENT2, which mediate plasma membrane nucleoside transport at pH 7.4, hENT3 is an acidic pH-activated lysosomal transporter partially localized to mitochondria. Recent studies demonstrate that hENT3 is indispensable for lysosomal homeostasis, and that mutations in hENT3 can result in a spectrum of lysosomal storage-like disorders...
July 20, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28722654/a-lectin-receptor-kinase-as-a-potential-sensor-for-extracellular-nicotinamide-adenine-dinucleotide-in-arabidopsis-thaliana
#5
Chenggang Wang, Mingqi Zhou, Xudong Zhang, Jin Yao, Yanping Zhang, Zhonglin Mou
Nicotinamide adenine dinucleotide (NAD(+)) participates in intracellular and extracellular signaling events unrelated to metabolism. In animals, purinergic receptors are required for extracellular NAD(+) (eNAD(+)) to evoke biological responses, indicating that eNAD(+) may be sensed by cell-surface receptors. However, the identity of eNAD(+)-binding receptors still remains elusive. Here, we identify a lectin receptor kinase (LecRK), LecRK-I.8, as a potential eNAD(+) receptor in Arabidopsis. The extracellular lectin domain of LecRK-I...
July 19, 2017: ELife
https://www.readbyqxmd.com/read/28722539/an-autophagy-driven-pathway-of-atp-secretion-supports-the-aggressive-phenotype-of-braf-v600e-inhibitor-resistant-metastatic-melanoma-cells
#6
Shaun Martin, Aleksandra M Dudek-Peric, Abhishek D Garg, Heleen Roose, Seyma Demirsoy, Sofie Van Eygen, Freya Mertens, Peter Vangheluwe, Hugo Vankelecom, Patrizia Agostinis
The ingrained capacity of melanoma cells to rapidly evolve towards an aggressive phenotype is manifested by their increased ability to develop drug-resistance, evident in the case of vemurafenib, a therapeutic-agent targeting BRAF(V600E). Previous studies indicated a tight correlation between heightened melanoma-associated macroautophagy/autophagy and acquired Vemurafenib resistance. However, how this vesicular trafficking pathway supports Vemurafenib resistance remains unclear. Here, using isogenic human and murine melanoma cell lines of Vemurafenib-resistant and patient-derived melanoma cells with primary resistance to the BRAF(V600E) inhibitor, we found that the enhanced migration and invasion of the resistant melanoma cells correlated with an enhanced autophagic capacity and autophagosome-mediated secretion of ATP...
July 19, 2017: Autophagy
https://www.readbyqxmd.com/read/28710541/injury-induced-purinergic-signalling-molecules-upregulate-pluripotency-gene-expression-and-mitotic-activity-of-progenitor-cells-in-the-zebrafish-retina
#7
Matías P Medrano, Claudio A Bejarano, Ariadna G Battista, Graciela D Venera, Ramón O Bernabeu, Maria Paula Faillace
Damage in fish activates retina repair that restores sight. The purinergic signalling system serves multiple homeostatic functions and has been implicated in cell cycle control of progenitor cells in the developing retina. We examined whether changes in the expression of purinergic molecules were instrumental in the proliferative phase after injury of adult zebrafish retinas with ouabain. P2RY1 messenger RNA (mRNA) increased early after injury and showed maximal levels at the time of peak progenitor cell proliferation...
July 14, 2017: Purinergic Signalling
https://www.readbyqxmd.com/read/28702845/regulation-of-cardiac-ca-2-and-ion-channels-by-shear-mechanotransduction
#8
REVIEW
Joon-Chul Kim, Min-Jeong Son, Jun Wang, Sun-Hee Woo
Cardiac contraction is controlled by a Ca(2+) signaling sequence that includes L-type Ca(2+) current-gated opening of Ca(2+) release channels (ryanodine receptors) in the sarcoplasmic reticulum (SR). Local Ca(2+) signaling in the atrium differs from that in the ventricle because atrial myocytes lack transverse tubules and have more abundant corbular SR. Myocardium is subjected to a variety of forces with each contraction, such as stretch, shear stress, and afterload, and adapts to those mechanical stresses...
July 12, 2017: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/28701358/mechanism-of-action-of-the-anti-inflammatory-connexin43-mimetic-peptide-jm2
#9
J Matthew Rhett, Bennett W Calder, Stephen A Fann, Heather Bainbridge, Robert G Gourdie, Michael J Yost
Connexin-based therapeutics have shown the potential for therapeutic efficacy in improving wound healing. Our previous work demonstrated that the connexin43 (Cx43)-mimetic peptide JM2 reduced the acute inflammatory response to a submuscular implant model by inhibiting purinergic signaling. Given the prospective application in improving tissue engineered construct tolerance that these results indicated, we sought to determine the mechanism of action for JM2 in the present study. Using confocal microscopy, a gap-FRAP cell communication assay, and an ethidium bromide uptake assay of hemichannel function we found that the peptide reduced cell-surface Cx43 levels, Cx43 gap junction (GJ) size, GJ communication, and hemichannel activity...
July 12, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/28699505/tackling-chronic-pain-and-inflammation-through-the-purinergic-system
#10
Giulia Magni, Daniele Riccio, Stefania Ceruti
The purinergic system is composed of purine and pyrimidine transmitters, of the enzymes that modulate the interconversion of nucleotides and nucleosides, of the membrane transporters that control their extracellular concentrations, and of the many receptor subtypes that are responsible for their cellular responses. The components of this system are ubiquitously localized in all tissues and organs, and their involvement in several physiological conditions has been clearly demonstrated. Moreover, extracellular purine and pyrimidine concentrations raise several folds under pathological conditions like tissue damage, ischemia, and inflammation, which suggest that this signaling system might contribute both to disease outcome and, possibly, to its tentative resolution...
July 10, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28697378/changes-in-phagocytosis-and-potassium-channel-activity-in-microglia-of-5xfad-mice-indicate-alterations-in-purinergic-signaling-in-a-mouse-model-of-alzheimer-s-disease
#11
Stefan Wendt, Meron Maricos, Natascha Vana, Niklas Meyer, Dilansu Guneykaya, Marcus Semtner, Helmut Kettenmann
As the immunocompetent cells of the central nervous system, microglia accumulate at amyloid beta plaques in Alzheimer's disease (AD) and acquire a morphological phenotype of activated microglia. Recent functional studies, however, indicate that in mouse models of amyloidosis and AD, these cells are rather dysfunctional indicated by a reduced phagocytic activity. Here, we report that this reduction in phagocytic activity is associated with perturbed purinergic receptor signaling, since phagocytosis could be stimulated by P2Y6 receptor activation in control, but not in 5xFAD transgenic animals, an animal model of amyloid deposition...
June 8, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28684613/endothelial-cell-autophagy-maintains-shear-stress-induced-nitric-oxide-generation-via-glycolysis-dependent-purinergic-signaling-to-endothelial-nitric-oxide-synthase
#12
Leena P Bharath, Jae Min Cho, Seul-Ki Park, Ting Ruan, Youyou Li, Robert Mueller, Tyler Bean, Van Reese, Russel S Richardson, Jinjin Cai, Ashot Sargsyan, Karla Pires, Pon Velayutham Anandh Babu, Sihem Boudina, Timothy E Graham, J David Symons
OBJECTIVE: Impaired endothelial cell (EC) autophagy compromises shear stress-induced nitric oxide (NO) generation. We determined the responsible mechanism. APPROACH AND RESULTS: On autophagy compromise in bovine aortic ECs exposed to shear stress, a decrease in glucose uptake and EC glycolysis attenuated ATP production. We hypothesized that decreased glycolysis-dependent purinergic signaling via P2Y1 (P2Y purinoceptor 1) receptors, secondary to impaired autophagy in ECs, prevents shear-induced phosphorylation of eNOS (endothelial nitric oxide synthase) at its positive regulatory site S1117 (p-eNOS(S1177)) and NO generation...
July 6, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28684291/lysine-demethylase-inhibition-protects-pancreatic-%C3%AE-cells-from-apoptosis-and-improves-%C3%AE-cell-function
#13
Marie Balslev Backe, Jan Legaard Andersson, Karl Bacos, Dan Ploug Christensen, Jakob Bondo Hansen, Jerzy Jòzef Dorosz, Michael Gajhede, Tina Dahlby, Madhusudhan Bysani, Line Hyltoft Kristensen, Charlotte Ling, Lars Olsen, Thomas Mandrup-Poulsen
Transcriptional changes control β-cell survival in response to inflammatory stress. Posttranslational modifications of histone and non-histone transcriptional regulators activate or repress gene transcription, but the link to cell-fate signaling is unclear. Inhibition of lysine deacetylases (KDACs) protects β cells from cytokine-induced apoptosis and reduces type 1 diabetes incidence in animals. We hypothesized that also lysine demethylases (KDMs) regulate β-cell fate in response to inflammatory stress. Expression of the demethylase Kdm6B was upregulated by proinflammatory cytokines suggesting a possible role in inflammation-induced β-cell destruction...
July 4, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28683062/use-of-luciferase-probes-to-measure-atp-in-living-cells-and-animals
#14
Giampaolo Morciano, Alba Clara Sarti, Saverio Marchi, Sonia Missiroli, Simonetta Falzoni, Lizzia Raffaghello, Vito Pistoia, Carlotta Giorgi, Francesco Di Virgilio, Paolo Pinton
ATP, the energy exchange factor that connects anabolism and catabolism, is required for major reactions and processes that occur in living cells, such as muscle contraction, phosphorylation and active transport. ATP is also the key molecule in extracellular purinergic signaling mechanisms, with an established crucial role in inflammation and several additional disease conditions. Here, we describe detailed protocols to measure the ATP concentration in isolated living cells and animals using luminescence techniques based on targeted luciferase probes...
August 2017: Nature Protocols
https://www.readbyqxmd.com/read/28667079/decreased-expression-of-connexin-43-blunts-the-progression-of-experimental-gn
#15
Panagiotis Kavvadas, Ahmed Abed, Coralie Poulain, Florence Authier, Lise-Paule Labéjof, Amelie Calmont, Carlo Afieri, Niki Prakoura, Jean-Claude Dussaule, Christos Chatziantoniou, Christos E Chadjichristos
GN refers to a variety of renal pathologies that often progress to ESRD, but the molecular mechanisms underlying this progression remain incompletely characterized. Here, we determined whether dysregulated expression of the gap junction protein connexin 43, which has been observed in the progression of renal disease, contributes to GN progression. Immunostaining revealed de novo expression of connexin 43 in damaged glomeruli in patients with glomerular diseases as well as in mice after induction of experimental GN...
June 30, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28659615/kca3-1-activation-via-p2y2-purinergic-receptors-promotes-human-ovarian-cancer-cell-skov-3-migration
#16
L Robles-Martínez, E Garay, M G Martel-Gallegos, A Cisneros-Mejorado, D Pérez-Montiel, A Lara, R O Arellano
Disorders in cell signaling mediated by ATP or histamine, activating specific membrane receptors, have been frequently associated with tumorigenesis. Among the elements of response to purinergic (and histaminergic) signaling, ion channel activation controls essential cellular processes in cancer, such as cell proliferation, motility, and death. Here, we studied the effects that ATP had on electrical properties of human ovarian adenocarcinoma cells named SKOV-3. ATP caused increase in intracellular Ca(2+) concentration ([Ca(2+)]i) and, concurrently, it evoked a complex electrical response with a conspicuous outward component...
June 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28658673/hyperthermia-and-associated-changes-in-membrane-fluidity-potentiate-p2x7-activation-to-promote-tumor-cell-death
#17
Paola de Andrade Mello, Shu Bian, Luiz Eduardo Baggio Savio, Haohai Zhang, Jingping Zhang, Wolfgang Junger, Márcia Rosângela Wink, Guido Lenz, Andréia Buffon, Yan Wu, Simon Christopher Robson
Extracellular ATP (eATP) accumulation within the tumor microenvironment (TME) has the potential to activate purinergic signaling. The eATP evoked signaling effects bolster antitumor immune responses while exerting direct cytotoxicity on tumor cells and vascular endothelial cells, mediated at least in part through P2X7 receptors. Approaches to augment purinergic signaling in TME e.g. by ectonucleotidase CD39 blockade, and/or boosting P2X7 functional responses, might be used as immunomodulatory therapies in cancer treatment...
June 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28652403/protease-activated-receptor-4-and-p2y12-dimerize-co-internalize-and-activate-akt-signaling-via-endosomal-recruitment-of-%C3%AE-arrestin
#18
Thomas H Smith, Julia G Li, Michael R Dores, JoAnn Trejo
Vascular inflammation and thrombosis requires the concerted actions of several different agonists, many of which act on G protein-coupled receptors (GPCRs). GPCR dimerization is a well-established phenomenon that can alter protomer function. In platelets and other cell types, protease-activated receptor-4 (PAR4) has been shown to dimerize with the purinergic receptor P2Y12 to coordinate β-arrestin-mediated Akt signaling, an important mediator of integrin activation. However, the mechanism by which the PAR4-P2Y12 dimer controls β-arrestin dependent Akt signaling is not known...
June 26, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28649232/ion-channels-of-pituitary-gonadotrophs-and-their-roles-in-signaling-and-secretion
#19
REVIEW
Stanko S Stojilkovic, Ivana Bjelobaba, Hana Zemkova
Gonadotrophs are basophilic cells of the anterior pituitary gland specialized to secrete gonadotropins in response to elevation in intracellular calcium concentration. These cells fire action potentials (APs) spontaneously, coupled with voltage-gated calcium influx of insufficient amplitude to trigger gonadotropin release. The spontaneous excitability of gonadotrophs reflects the expression of voltage-gated sodium, calcium, potassium, non-selective cation-conducting, and chloride channels at their plasma membrane (PM)...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/28648830/purinergic-p2y-receptors-molecular-diversity-and-implications-for-treatment-of-cardiovascular-diseases
#20
REVIEW
Akiyuki Nishimura, Caroline Sunggip, Sayaka Oda, Takuro Numaga-Tomita, Makoto Tsuda, Motohiro Nishida
Purinergic signaling, mediated mainly by G protein-coupled P2Y receptors (P2YRs), is now attracting attention as a new therapeutic target for preventing or treating cardiovascular diseases. Observations using mice with genetically modified P2YRs and/or treated with a pharmacological P2YR inhibitor have helped us understand the physiological and pathological significance of P2YRs in the cardiovascular system. P2YR-mediated biological functions are predominantly activated by mononucleotides released from non-adrenergic, non-cholinergic nerve endings or non-secretory tissues in response to physical stress or cell injury, though recent studies have suggested the occurrence of ligand-independent P2YR function through receptor-receptor interactions (oligomerization) in several biological processes...
June 23, 2017: Pharmacology & Therapeutics
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