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Molecular Pharmacology

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https://www.readbyqxmd.com/read/28495999/%C3%AE-arrestin-mediated-regulation-of-the-human-ether-a-go-go-related-gene-herg-potassium-channel
#1
Matthew G Sangoi, Shawn M Lamothe, Jun Guo, Tonghua Yang, Wentao Li, Ellen G Avery, John T Fisher, Shetuan Zhang
The rapidly activating delayed rectifier K(+) channel (IKr) is encoded by the human ether-a-go-go-related gene (hERG), which is important for the repolarization of the cardiac action potential. Mutations in hERG or drugs can impair the function or decrease the expression level of hERG channels, leading to long QT syndrome (LQTS). Thus, it is important to understand hERG channel trafficking and its regulation. For this purpose, G protein-coupled receptors (GPCRs), which regulate a vast array of cellular processes, represent a useful route...
May 11, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28468946/novel-mode-of-antagonist-binding-in-nmda-receptors-revealed-by-the-crystal-structure-of-the-glun1-glun2a-ligand-binding-domain-complexed-to-nvp-aam077
#2
Annabel Romero-Hernandez, Hiro Furukawa
Competitive antagonists against N-methyl-D-aspartate (NMDA) receptors have played critical roles throughout the history of neuropharmacology and basic neuroscience. There are currently numerous NMDA receptor antagonists containing a variety of chemical groups. Among those compounds, a GluN2-specific antagonist, (R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl]-phosphonic acid (NVP-AAM077), contains a unique combination of a dioxoquinoxalinyl ring, a bromophenyl group, and a phosphono group...
May 3, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28461586/dexamethasone-down-regulates-endothelin-receptors-and-reduces-endothelin-induced-production-of-matrix-metalloproteinases-in-cultured-rat-astrocytes
#3
Yutaka Koyama, Ayano Ukita, Kana Abe, Kuniaki Iwamae, Shogo Tokuyama, Keisuke Tanaka, Yuki Kotake
In brain disorders, astrocytes change phenotype to reactive astrocytes, and are involved in the induction of neuroinflammation and brain edema. The administration of glucocorticoids (GCs), such as dexamethasone (Dex), reduces astrocytic activation, but the mechanisms underlying this inhibitory action are not well understood. Endothelins (ETs) promote astrocytic activation. Therefore, the effects of Dex on ET receptor expressions were examined in cultured rat astrocytes. Treatment with 300 nM Dex for 6 - 48 hours reduced the mRNA expression of astrocytic ETA and ETB receptors to 30-40 % of non-treated cells...
May 1, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28461585/upregulated-ectonucleotidases-in-fadd-and-rip1-deficient-jurkat-leukemia-cells-counteract-extracellular-atp-amp-accumulation-via-pannexin-1-channels-during-chemotherapeutic-drug-induced-apoptosis
#4
Andrea M Boyd-Tressler, Graham S Lane, George R Dubyak
Pannexin-1 (Panx1) channels mediate the efflux of ATP and AMP from cancer cells in response to induction of extrinsic apoptosis by death receptors or intrinsic apoptosis by chemotherapeutic agents. We previously described the accumulation of extracellular ATP /AMP during chemotherapy-induced apoptosis in Jurkat human leukemia cells. In this study, we compared how different signaling pathways determine extracellular nucleotide pools in control Jurkat cells versus Jurkat lines that lack the FADD or RIP1 cell death regulatory proteins...
May 1, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28442602/molecular-basis-of-metabolism-mediated-conversion-of-pk11195-from-an-antagonist-to-an-agonist-of-the-constitutive-androstane-receptor
#5
Bryan Mackowiak, Linhao Li, Matthew A Welch, Daochuan Li, Jace W Jones, Scott Heyward, Maureen A Kane, Peter W Swaan, Hongbing Wang
The constitutive androstane receptor (CAR) plays an important role in xenobiotic metabolism, energy homeostasis, and cell proliferation. Antagonism of CAR represents a key strategy for studying its function and may have potential clinical applications. However, specific human CAR (hCAR) antagonists are limited and conflicting data on the activity of these compounds have been reported. PK11195, a typical peripheral benzodiazepine receptor ligand, has been established as a potent hCAR deactivator in immortalized cells; whether it inhibits hCAR activity under physiologically-relevant conditions remains unclear...
April 25, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28432201/mg53-biological-function-and-potential-as-a-therapeutic-target
#6
Yan Zhang, Hong-Kun Wu, Fengxiang Lv, Rui-Ping Xiao
MG53 (also known as TRIM72) is a cardiac and skeletal muscle-specific TRIM-family protein that exhibits multiple biological functions. First, MG53 participates in plasma membrane repair of the heart, skeletal muscle and other tissues. Second, MG53 is essentially involved in the cardioprotection of cardiac ischemic, pre-conditioning and post-conditioning, by activating the PI3K-Akt-GSK3β and ERK1/2 survival signaling pathways. Moreover, systemic delivery of recombinant MG53 protein ameliorates the impact of a range of injury insults on heart, skeletal muscle, lung, kidney, skin and brain...
April 21, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28428226/rapid-throughput-analysis-of-gabaa-receptor-subtype-modulators-and-blockers-using-disbac1-3-membrane-potential-red-dye
#7
Atefeh Mousavi Nik, Brandon Pressly, Vikrant Singh, Shane Antrobus, Susan Hulsizer, Michael A Rogawski, Heike Wulff, Isaac N Pessah
Fluorometric Imaging Plate Reader (FLIPR®) membrane potential dye (FMP-Red-Dye) is a proprietary tool for basic discovery and high throughput drug screening for G-protein coupled receptors and ion channels. We optimized and validated this potentiometric probe to assay functional modulators of heterologous expressed GABAA receptor (GABAAR) isoforms (synaptic α1β3γ2, extrasynaptic α4β3δ, and β3 homopentomers). High-resolution mass spectrometry identified FMP-Red-dye as DisSBAC1(3). GABAAR expressing cells equilibrated with FMP-Red-Dye exhibited depolarized equilibrium membrane (Em) potentials compared to GABAAR-null cells...
April 20, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28424220/gababr-induced-egfr-transactivation-promotes-migration-of-human-prostate-cancer-cells
#8
Shuai Xia, Cong He, Yini Zhu, Suyun Wang, Huiping Li, Zhongling Zhang, Xinnong Jiang, Jianfeng Liu
G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) act in concert to regulate cell growth, proliferation, survival, and migration. Metabotropic GABAB receptor (GABABR) is the GPCR for the main inhibitory neurotransmitter GABA in the central nervous system. Increased expression of GABABR has been detected in human cancer tissues and cancer cell lines, but the role of GABABR in these cells is controversial and the underlying mechanism remains poorly understood. Here, we investigated whether GABABR hijacks RTK signaling to modulate the fates of human prostate cancer cells...
April 19, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28420679/tumor-microenvironment-targeting-and-responsive-peptide-based-nanoformulations-for-improved-tumor-therapy
#9
Hao Qin, Yanping Ding, Ayeesha Mujeeb, Ying Zhao, Guangjun Nie
Tumor microenvironment participates in all stages of tumor progression and has emerged as a promising therapeutic target for cancer therapy. Rapid progress in the field of molecular self-assembly using various biological molecules has resulted in the fabrication of nanoformulations, specifically targeting and regulating the microenvironment components to inhibit tumor malignancies. This inhibition process is based on the differentiating biophysicochemical cues guiding tumor and normal tissue microenvironments...
April 18, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28416574/a-glutamate-substituted-mutant-mimics-the-phosphorylated-and-active-form-of-guanylyl-cyclase-a
#10
Neil M Otto, William G McDowell, Deborah M Dickey, Lincoln R Potter
Multisite phosphorylation is required for activation of guanylyl cyclase (GC)-A, also known as NPR-A or NPR1, by cardiac natriuretic peptides (NPs). Seven chemically identified sites (Ser-487, Ser-497, Thr-500, Ser-502, Ser-506, Ser-510, Thr-513) and one functionally identified putative site (Ser-473) were reported. Single alanine substitutions for Ser-497, Thr-500, Ser-502, Ser-506 and Ser-510 reduced maximal velocity (Vmax), while glutamate substitutions had no effect or increased Vmax. Ala but not Glu substitution for Ser-497 increased the Michaelis constant (Km) ~400%...
April 17, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28408657/negative-regulation-of-human-pregnane-x-receptor-by-microrna-18a-5p-evidence-for-suppression-of-microrna-18a-5p-expression-by-rifampin-and-rilpivirine
#11
Devinder Sharma, Abdullah A Turkistani, Wenjun Chang, Catherine Hu, Zhaoming Xu, Thomas K H Chang
Small non-coding microRNAs act as post-transcriptional regulators of gene expression involved in diverse biological functions. Pregnane X receptor (PXR, NR1I2), which is a member of the superfamily of nuclear receptors, is a transcription factor governing the transport and biotransformation of various endobiotics and xenobiotics. In the present study, we identified a specific microRNA involved in regulating the expression and functionality of human PXR (hPXR). According to bioinformatics analysis employing three commonly used algorithms (TargetScan, miRanda, and DIANA-microT-CDS), miR-18a-5p was predicted to be the top candidate microRNA regulator of hPXR...
April 13, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28404616/progress-of-pharmacological-sciences-in-china
#12
Jian-Cheng Wang, Yungui Zhu, Lei Wu, Erdan Dong
Pharmacology is the science that investigates the interactions between organisms and drugs and their mechanisms. Pharmacology plays a translational role in modern medicine, bridging basic research to the clinic. With its booming economy, China has invested an enormous amount of financial and human resources on pharmacological research in the recent decade. As a result, major breakthroughs have been achieved in both basic and clinical research in this area with the discoveries of many potential drug targets and biomarkers, making a sizable contribution to the overall advancement of pharmacological sciences...
April 12, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28396564/structural-analysis-of-the-glucocorticoid-receptor-ligand-binding-domain-in-complex-with-triamcinolone-acetonide-and-a-fragment-of-the-atypical-coregulator-shp
#13
Emily R Weikum, Denise C Okafor, Emma H D'Agostino, Jennifer K Colucci, Eric A Ortlund
The synthetic glucocorticoids (GCs) dexamethasone, mometasone furoate, and triamcinolone acetonide have been pharmaceutical mainstays to treat chronic inflammatory diseases. These drugs bind to the glucocorticoid receptor (GR), a ligand- activated transcription factor and member of the nuclear receptor superfamily. GR is widely recognized as a therapeutic target for its ability to counter pro-inflammatory signaling. Despite the popularity of GCs in the clinic, long-term use leads to numerous side effects, driving the need for new and improved drugs with less off-target pharmacology...
April 10, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28385906/probe-dependent-negative-allosteric-modulators-of-the-long-chain-free-fatty-acid-receptor-ffa4
#14
Kenneth R Watterson, Steffen V F Hansen, Brian Hudson, Elisa Alvarez-Curto, Sheikh Z Raihan, Carlos M G Azevedo, Gabriel Martin, Julia Dunlop, Stephen J Yarwood, Trond Ulven, Graeme Milligan
High affinity and selective antagonists that are able to block the actions of both endogenous and synthetic agonists of G protein-coupled receptors are integral to analysis of receptor function and to support suggestions of therapeutic potential. Although there is great interest in the potential of free fatty acid receptor 4 (FFA4) as a novel therapeutic target for the treatment of type II diabetes, the broad distribution pattern of this receptor suggests it may play a range of roles beyond glucose homeostasis in different cells and tissues...
April 6, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28385905/in-vivo-characterization-of-an-ahr-dependent-long-non-coding-rna-required-for-proper-sox9b-expression
#15
Gloria R Garcia, Britton C Goodale, Michelle W Wiley, Jane K La Du, David A Hendrix, Robert L Tanguay
Xenobiotic activation of the aryl hydrocarbon receptor (AHR) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) prevents the proper formation of craniofacial cartilage and the heart in developing zebrafish. Downstream molecular targets responsible for AHR-dependent adverse effects remain largely unknown; however, in zebrafish sox9b has been identified as one of the most reduced transcripts in several target organs and is hypothesized to have a causal role in TCDD-induced toxicity. The reduction of sox9b expression in TCDD-exposed zebrafish embryos has been shown to contribute to heart and jaw malformation phenotypes...
April 6, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28377424/the-ca2-permeable-cation-trpv3-channel-an-emerging-pivotal-target-for-itch-and-skin-diseases
#16
Gongxin Wang, Kewei Wang
Temperature-sensitive transient receptor potential (thermo-TRP) channels such as TRPA1 and TRPV1 have been indicated as downstream ion channel targets in transduction of itch. As a member of thermos-TRPs, Ca2+-permeable nonselective cation TRPV3 channels are expressed abundantly in the skin keratinocytes. Recent identification of gain-of-function mutations of human TRPV3 from patients with Olmsted Syndrome characterized by severe itching and palmoplantar and periorificial keratoderma unveils its crucial role in chronic itch and skin diseases...
April 4, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28363985/structure-and-dynamics-of-the-liver-receptor-homolog-1-pgc1%C3%AE-complex
#17
Suzanne G Mays, C Denise Okafor, Micheal L Tuntland, Richard J Whitby, Venkatasubramanian Dharmarajan, Jozef Stec, Patrick R Griffin, Eric A Ortlund
Peroxisome proliferator-activated gamma coactivator 1-α (PGC1α) regulates energy metabolism by directly interacting with transcription factors to modulate gene expression. Among the PGC1α binding partners is Liver receptor homolog 1 (LRH-1; NR5A2), an orphan nuclear hormone receptor that controls lipid and glucose homeostasis. Although PGC1α is known to bind and activate LRH-1, mechanisms through which PGC1α changes LRH-1 conformation to drive transcription are unknown. Here, we used biochemical and structural methods to interrogate the LRH-1-PGC1α complex...
March 31, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28360094/identification-and-structure-function-study-of-positive-allosteric-modulators-of-kainate-receptors
#18
Anja Probst Larsen, Sabine Fievre, Karla Frydenvang, Pierre Francotte, Bernard Pirotte, Jette Sandholm Karstrup, Christophe Mulle
Kainate receptors (KARs) consist of a class of ionotropic glutamate receptors, which exert diverse pre- and postsynaptic functions through complex signaling regulating the activity of neural circuits. Whereas numerous small-molecule positive allosteric modulators of the ligand-binding domain of AMPA receptors have been reported, no such ligands are available for KARs. In this study, we have investigated the ability of three benzothiadiazine-based modulators to potentiate glutamate-evoked currents at recombinantly expressed KARs...
March 30, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28356334/clinical-applications-of-circulating-tumor-cells-in-pharmacotherapy-challenges-and-perspectives
#19
Tong Wu, Bin Cheng, Liwu Fu
Circulating tumor cells (CTCs) have been identified as one of the ultrasensitive liquid biopsy for real-time monitoring cancer patients. The CTCs detection in peripheral blood from cancer patients has brought the hope, but still facing serious challenge on its specificity and sensitivity. Here, we review the significant roles of CTCs in metastasis, and the strength and weakness of currently available methods for CTCs detection and characterization. Moreover, we mainly discuss the clinical application of CTCs such as markers for patients' prognosis prediction, and we specifically focus on the application of CTCs as indicators in cancer pharmacotherapy...
March 29, 2017: Molecular Pharmacology
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
#20
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
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