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Molecular Pharmacology

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https://www.readbyqxmd.com/read/28331048/g-protein-coupled-receptor-kinase-3-and-protein-kinase-c-phosphorylate-the-distal-c-terminal-tail-of-the-chemokine-receptor-cxcr4-and-mediate-recruitment-of-beta-arrestin
#1
Jiansong Luo, John M Busillo, Ralf Stumm, Jeffrey L Benovic
Phosphorylation of G protein-coupled receptors (GPCRs) is a key event for cell signaling and regulation of receptor function. Previously, using tandem mass spectrometry, we identified two phosphorylation sites at the distal C-terminal tail of the chemokine receptor CXCR4, but were unable to determine which specific residues were phosphorylated. Here, we demonstrate that serines 346 and/or 347 (Ser-346/7) of CXCR4 are phosphorylated upon stimulation with the agonist CXCL12 as well as a CXCR4 pepducin, ATI-2341...
March 22, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28325748/halogenated-ether-alcohol-and-alkane-anesthetics-activate-task-3-tandem-pore-potassium-channels-likely-through-a-common-mechanism
#2
Anita Luethy, James D Boghosian, Rithu Srikantha, Joseph Cotten
TASK-3 (KCNK9) tandem pore potassium channel function is activated by halogenated anesthetics through binding at a putative anesthetic binding cavity. To understand pharmacological requirements for TASK-3 activation, we studied the concentration-response of TASK-3 to several anesthetics (isoflurane, desflurane, sevoflurane, halothane, α-chloralose, 2,2,2-trichloroethanol(TCE), and chloral hydrate), to ethanol, and to a panel of halogenated methanes and alcohols. We used mutagenesis to probe the anesthetic binding cavity as observed in a TASK-3 homology model...
March 21, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28320780/thiosemicarbazones-functioning-as-zinc-metallochaperones-to-reactivate-mutant-p53
#3
Xin Yu, Adam R Blanden, Ashley Tsang, Saif Zaman, Yue Liu, John Gilleran, Anthony F Bencivenga, S David Kimball, Stewart N Loh, Darren R Carpizo
Small molecule restoration of wild type structure and function to mutant p53 (so - called mutant reactivation) is a highly sought after goal in cancer drug development. We previously discovered small molecule zinc chelators called zinc metallochaperones (ZMCs) reactivate mutant p53 by restoring zinc binding to zinc deficient p53 mutants. The lead compound identified from the NCI-60 human tumor cell lines screen, NSC319726 (ZMC1), belongs to the thiosemicarbazone (TSC) class of metal ion chelators that bind Fe, Cu, Mn, Zn, and other transition metals...
March 20, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28314853/activation-of-the-orphan-g-protein-coupled-receptor-gpr27-by-surrogate-ligands-promotes-%C3%AE-arrestin-2-recruitment
#4
Nadine Dupuis, Celine Laschet, Delphine Franssen, Martyna Szpakowska, Julie Gilissen, Pierre Geubelle, Arvind Soni, Anne-Simone Parent, Bernard Pirotte, Andy Chevigne, Jean-Claude Twizere, Julien Hanson
G protein-coupled receptors are the most important drug targets for human diseases. An important number of them remain devoid of confirmed ligands. GPR27 is one of these orphan receptors, characterized by a high level of conservation among vertebrates and a predominant expression in the central nervous system. In addition, it has recently been linked to insulin secretion. However, the absence of endogenous or surrogate ligands for GPR27 complicates the examination of its biological function. Our aim was to validate GPR27 signaling pathways and therefore we sought to screen a diversity oriented synthesis library to identify GPR27-specific surrogate agonists...
March 17, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28283555/developmental-genetic-dietary-and-xenobiotic-influences-on-neonatal-hyperbilirubinemia
#5
Mei-Fei Yueh, Shujuan Chen, Nghia Nguyen, Robert H Tukey
Hyperbilirubinemia, caused by the accumulation of unconjugated bilirubin, is one of the most common clinical diagnoses in both premature and term newborns. Owing to the fact that bilirubin is metabolized solely through glucuronidation by UDP-glucuronosyltransferase (UGT) 1A1, it is now known that immaturity of UGT1A1 in combination with overproduction of bilirubin during the developmental stage acts as a bottleneck to bilirubin elimination and predisposes the infant to high TBS levels. While neonatal jaundice is mostly benign, excessively high levels of serum bilirubin in a small percentage of newborns can cause bilirubin-induced neurologic dysfunction (BIND), potentially leading to permanent brain damage, a condition known as kernicterus...
March 10, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28283554/impaired-dual-specificity-protein-phosphatase-dusp4-reduces-corticosteroid-sensitivity
#6
Yoshiki Kobayashi, Kazuhiro Ito, Akira Kanda, Koich Tomoda, Nicolas Mercado, Peter Barnes
We have reported that phosphorylation of glucocorticoid receptor (GR) at Ser(226) reduces GR nuclear translocation resulting in corticosteroid insensitivity in patients with severe asthmas. A serine/threonine protein phosphatase, PP2A, which regulates JNK1 and GR-Ser(226) signaling, is involved in this mechanism. Here, we further explored dual-specificity protein kinases (DUSPs) with the ability to dephosphorylate JNK, and identified DUSP4 as a phosphatase involved in the regulation of corticosteroid sensitivity...
March 10, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28280061/purinergic-receptor-transactivation-by-the-%C3%AE-2-adrenergic-receptor-increases-intracellular-ca-2-in-non-excitable-cells
#7
Wayne Stallaert, Emma T van der Westhuizen, Anne-Marie Schonegge, Bianca Plouffe, Mireille Hogue, Viktoria Lukashova, Asuka Inoue, Satoru Ishida, Junken Aoki, Christian Le Gouill, Michel Bouvier
The β2 adrenergic receptor (β2AR) increases intracellular Ca(2+) in a variety of cell types. By combining pharmacological and genetic manipulations, we reveal a novel mechanism through which the β2AR promotes Ca(2+) mobilization (pEC50 = 7.32 ± 0.10) in non-excitable human embryonic kidney (HEK)-293S cells. Down-regulation of Gs with sustained cholera toxin pre-treatment and the use Gs-null HEK293 (ΔGs-HEK293) cells generated using the CRISPR/Cas9 system, combined with pharmacological modulation of cAMP formation revealed a Gs-dependent but cAMP-independent increase in intracellular Ca(2+) following β2AR stimulation...
March 9, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28275050/novel-thiosemicarbazones-inhibit-lysine-rich-ceacam1-co-isolated-lyric-and-the-lyric-induced-epithelial-mesenchymal-transition-via-up-regulation-of-n-myc-downstream-regulated-gene-1-ndrg1
#8
Ruxing Xi, Ivan Ho Yuen Pun, Sharleen V Menezes, Leyla Fouani, Danuta S Kalinowski, Michael L H Huang, Xiaozhi Zhang, Des R Richardson, Zaklina Kovacevic
Tumor necrosis factor α (TNFα) plays a vital role in cancer progression, being associated with inflammation and promotion of cancer angiogenesis and metastasis. The effects of TNFα are mediated by its down-stream target, the oncogene, lysine-rich CEACAM1 co-isolated protein (LYRIC; also known as metadherin or astrocyte elevated gene-1). LYRIC plays an important role in activating the nuclear factor-κB (NF-κB) signaling pathway, which controls multiple cellular processes, including proliferation, apoptosis, migration, etc...
March 8, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28275049/the-antineoplastic-activity-of-bardoxolone-methyl-and-a-related-triterpenoid-in-leukemia-cells-is-due-to-reactive-oxygen-species-dependent-suppression-of-cmyc
#9
Unho Jin, Yating Cheng, Beiyan Zhou, Stephen Safe
Structurally-related pentacyclic triterpenoids methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate [Bardoxolone-methyl (Bar-Me)] and methyl 2-trifluoromethyl-3,11-dioxoolean-1,12-dien-30-oate (CF3DODA-Me) contain 2-cyano-1-en-3-one and 2-trifluoromethyl-1-en-3-one moieties, respectively, in their A rings and differ in the position of their en-one structures in ring C. Only Bar-Me forms a Michael addition adduct with glutathione and inhibits IKKβ phosphorylation and these differences may be due to steric hinderance by the 11-keto group in CF3DODA-Me which prevents Michael addition by the conjugated en-one in the A-ring...
March 8, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28265019/the-first-negative-allosteric-modulator-for-dopamine-d2-and-d3-receptors-sb269652-may-lead-to-a-new-generation-of-antipsychotic-drugs
#10
Mario Rossi, Irene Fasciani, Francesco Marampon, Roberto Maggio, Marco Scarselli
D2 and D3 dopamine receptors belong to the largest family of cell surface proteins in eukaryotes, the G protein-coupled receptors (GPCRs). Considering their crucial physiological functions and their relatively accessible cellular locations, GPCRs represent one of the most important classes of therapeutic targets. Until recently, the only strategy to develop drugs regulating GPCR activity was through the identification of compounds that directly acted on the orthosteric sites for endogenous ligands. However, many efforts have recently been made in order to identify small molecules that are able to interact with allosteric sites...
March 6, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28254957/the-orphan-receptor-gpr17-is-unresponsive-to-uracil-nucleotides-and-cysteinyl-leukotrienes
#11
Katharina Simon, Nicole Merten, Ralf Schroder, Stephanie Hennen, Philip Preis, Nina-Katharina Schmitt, Lucas Peters, Ramona Schrage, Celine Vermeiren, Michel Gillard, Klaus Mohr, Jesus Gomeza, Evi Kostenis
Pairing orphan G protein-coupled receptors (GPCRs) with their cognate endogenous ligands is expected to have a major impact on our understanding of GPCR biology. It follows that reproducibility of orphan receptor ligand pairs should be of fundamental importance to guide meaningful investigations into pharmacology and function of individual receptors. GPR17 is an orphan receptor characterized by some as dualistic uracil-nucleotide/cysteinyl-leukotriene receptor and by others as inactive towards these stimuli altogether...
March 2, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28246190/phosphorylation-of-g-protein-coupled-receptors-from-the-barcode-hypothesis-to-the-flute-model
#12
Zhao Yang, Fan Yang, Daolai Zhang, Zhixin Liu, Amy Lin, Chuan Liu, Peng Xiao, Xiao Yu, Jin-Peng Sun
Seven transmembrane G protein-coupled receptors (GPCRs) are often phosphorylated at the C-terminus and on intracellular loops in response to various extracellular stimuli. Phosphorylation of GPCRs by GPCR kinases (GRKs) and certain other kinases can promote the recruitment of arrestin molecules. The arrestins critically regulate GPCR functions, not only by mediating receptor desensitization and internalization, but also by redirecting signalling to G protein-independent pathways via interactions with numerous downstream effector molecules...
February 28, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28246189/aee788-inhibits-basal-body-assembly-and-blocks-dna-replication-in-the-african-trypanosome
#13
Catherine Sullenberger, Daniel Pique, Yuko Ogata, Kojo Mensa-Wilmot
Trypanosoma brucei causes human African trypanosomiasis (HAT). The pyrrolopyrimidine AEE788 (a hit for anti-HAT drug discovery) associates with three trypanosome protein kinases. Herein we delineate the effects of AEE788 on T. brucei using chemical biology strategies. AEE788 treatment inhibits DNA replication in the kinetoplast (mitochondrial nucleoid) and nucleus. In addition, AEE788 blocks duplication of the basal body and the bilobe without affecting mitosis. Thus, AEE788 prevents entry into S phase of the cell division cycle...
February 28, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28242743/advances-in-hypoxia-mediated-mechanisms-in-hepatocellular-carcinoma
#14
Xin Xin Xiong, Xin Yao Qiu, Dian Xing Hu, Xiao Qian Chen
Hepatocellular carcinoma (HCC) is the fifth most common and the third most deadly malignant tumor worldwide. Hypoxia and related oxidative stress are heavily involved in the process of HCC development and therapies. However, direct and accurate measuring oxygen concentration and evaluating hypoxic effects in HCC prove difficult. Moreover, the hypoxia-mediated mechanisms in HCC remain elusive. Here, we summarize recent major evidence of hypoxia in HCC lesions by measuring pO2, the clinical importance of hypoxic markers in HCC, and recent advances in hypoxia-related mechanisms and therapies in HCC...
February 27, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28213589/sh479-a-betulinic-acid-derivative-ameliorates-experimental-autoimmune-encephalomyelitis-by-regulating-the-th17-treg-balance
#15
Jing Li, Ji Jing, Yang Bai, Zhen Li, Roumei Xing, Binhe Tan, Xueyun Ma, Wenwei Qiu, Changsheng Du, Bing Du, Fan Yang, Jie Tang, Stefan Siwko, Mingyao Liu, Huaqing Chen, Jian Luo
CD4+ T helper cells, especially Th17 cells, combined with immune regulatory network dysfunction, play key roles in autoimmune diseases including multiple sclerosis (MS). Betulinic acid (BA), a natural pentacyclic triterpenoid, has been reported to be involved in anti-inflammation, in particular having an inhibitory effect on pro-inflammatory cytokine IL-17 and IFN-γ production. In this study, we screened BA derivatives and found a BA derivative, SH479, which had a greater inhibitory effect on Th17 differentiation...
February 17, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28202578/p38%C3%AE-mapk-signaling-mediates-exenatide-stimulated-microglial-%C3%AE-endorphin-expression
#16
Hai-Yun Wu, Xiao-Fang Mao, Hui Fan, Yong-Xiang Wang
Upon recent discovery, it has been established that activation of glucagon-like peptide-1 receptors (GLP-1Rs) exhibits neuroprotection and antinociception through microglial β-endorphin expression. This study aims to explore its underlying signaling mechanisms. GLP-1Rs and β-endorphin were co-expressed in primary cultures of microglia. Treatment with the GLP-1R agonist exenatide concentration-dependently stimulated microglial expression of the β-endorphin precursor gene POMC and peptide, with EC50 values of 4...
February 15, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28193640/grk2-mediates-arginine-vasopressin-induced-il-6-production-via-nf-kb-signaling-in-neonatal-rat-cardiac-fibroblast
#17
Feifei Xu, Suzhen Sun, Xiaojun Wang, Eran Ni, Lingling Zhao, Weizhong Zhu
Elevated interleukin 6(IL-6) levels in congestive heart failure are associated with myocardial damage during acute exacerbation and with chronic inflammation. Arginine vasopressin (AVP), a hormone released in response to cardiac stress, could be a factor of inflammation and fibrosis in the pathogenesis of heart failure. Recently, we have shown that AVP promotes the proliferation of neonatal rat cardiac fibroblasts (NRCFs) through a V1Avasopressin receptor-mediated G protein-coupled receptor kinase2 (GRK2) signaling...
February 13, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28188254/differential-effects-of-oxytocin-receptor-antagonists-atosiban-and-nolasiban-on-ot-mediated-signalling-in-human-amnion-and-myometrium
#18
Sung Hye Kim, Oliver Pohl, Andre Chollet, Jean-Pierre Gotteland, Adam D J Fairhurst, Phillip R Bennett, Vasso Terzidou
One of the most established roles of oxytocin (OT) is in inducing uterine contractions and labour. Apart from contractions, our recent study have shown that OT can also activate pro-inflammatory pathways in both human myometrial and amnion cells which suggests the pro-inflammatory role of OT should be taken into account when developing tocolytics targeting the OT/OT receptor (OT/OTR) system. The OTR antagonist, Atosiban, is currently used therapeutically for the treatment of PTL. We have previously shown that Atosiban fails to inhibit the pro-inflammatory effects of OT in human amnion, and Atosiban alone activates NF-κB and MAPKs thus upregulating downstream pro-labour genes...
February 10, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28153854/sequence-specific-regulation-of-endocytic-lifetimes-modulates-arrestin-mediated-signaling-at-the-%C3%AE-opioid-receptor
#19
Zara Y Weinberg, Amanda S Zajac, Tiffany Phan, Daniel J Shiwarski, Manojkumar A Puthenveedu
Functional selectivity at the μ opioid receptor (μR), a prototypical GPCR that is a physiologically relevant target for endogenous opioid neurotransmitters and analgesics, has been a major focus for drug discovery in the recent past. The cellular mechanisms that mediate functional selectivity, however, are still being fully elucidated. The present work tested the hypothesis that lifetimes of agonist-induced receptor-arrestin clusters at the cell surface controls the magnitude of arrestin signaling, and therefore functional selectivity, on μR...
February 2, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28153853/epigenetic-activation-of-mu-opioid-receptor-mor-gene-via-increased-expression-and-function-of-mitogen-and-stress-activated-protein-kinase-1-msk1
#20
Yadav Wagley, Ping-Yee Law, Li-Na Wei, Horace H Loh
Since the discovery of mu opioid receptor (MOR) gene two decades ago, various regulatory factors have been shown to interact with the MOR promoter and modulate transcript levels. However, the majority of early transcriptional studies on MOR gene have not addressed how intracellular signaling pathways mediate extracellular modulators. In this study, we demonstrate that MOR epigenetic regulation requires multiple co-ordinated signals converged at the MOR promoter, involving mitogen-activated protein kinase (MAPK) activation and mitogen-and stress-activated protein kinase (MSK1) - similar ranges of intracellular signaling pathways that are activated by opioid agonists...
February 2, 2017: Molecular Pharmacology
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