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Molecular Pharmacology

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https://www.readbyqxmd.com/read/29150461/gabaa-receptor-activation-in-the-allosteric-coagonist-model-framework-relationship-between-ec50-and-basal-activity
#1
Gustav Akk, Daniel J Shin, Allison L Germann, Joseph H Steinbach
The concerted transition model for multimeric proteins is a simple formulation for analyzing the behavior of transmitter-gated ion channels. Here, we use the model to examine the relationship between the EC50 for activation of the GABAA receptor by the transmitter GABA and basal activity employing concatemeric ternary GABAA receptors expressed in Xenopus oocytes. The basal activity reflects receptor function in the absence of transmitter, and can be changed either by mutation to increase constitutive activity, or by addition of a second agonist (acting at a different site) to increase background activity...
November 17, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29142019/molecular-imaging-of-glut1-and-glut5-in-breast-cancer-a-multitracer-pet-imaging-study-in-mice
#2
Melinda Wuest, Ingrit Hamann, Vincent Bouvet, Darryl Glubrecht, Alison Marshall, Brendan Trayner, Olivier Soueidan, Daniel Krys, Michael Wagner, Chris Cheeseman, Frederick West, Frank Wuest
Use of [18F]FDG-PET in clinical breast cancer (BC) imaging is limited mainly due to insufficient expression levels of GLUT1 in up to 50% of all patients. Fructose-specific facilitative hexose transporter GLUT5 represents an alternative biomarker for PET imaging of hexose metabolism in BC. The goal of the present study was to compare uptake characteristics of selected hexose-based PET radiotracers in murine BC model EMT6. Uptake of 1-deoxy-1-[18F]fluoro-D-fructose (1-[18F]FDF), 6-deoxy-6-[18F]fluoro-D-fructose (6-[18F]FDF), 1-deoxy-1-[18F]fluoro-2,5-anhydro-mannitol (1-[18F]FDAM), 2-deoxy-2-[18F]fluoro-D-glucose (2-[18F]FDG) and 6-deoxy-6-[18F]fluoro-D-glucose (6-[18F]FDG) was studied in EMT6 cells, tumors and muscle and correlated to GLUT1 and GLUT5 expression levels...
November 15, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29138269/irreversible-activation-and-stabilization-of-soluble-guanylate-cyclase-by-the-protoporphyrin-ix-mimetic-cinaciguat
#3
Alexander Kollau, Marissa Opelt, Gerald Wölkart, Antonius C F Gorren, Michael Russwurm, Doris Koesling, Bernd Mayer, Astrid Schrammel
Belonging to the class of so-called sGC activators, cinaciguat and BAY 60-2770 are interesting therapeutic tools for the treatment of various cardiovascular pathologies. The drugs are supposed to preferentially stimulate oxidized or heme-depleted but not native sGC. Since this concept has been challenged by studies demonstrating complete relaxation of non-diseased vessels, this study was designed to re-investigate the mode of action in greater detail. To this purpose, the effect of cinaciguat was studied on vessel tone of porcine coronary arteries and rat thoracic aortas...
November 14, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29138268/n-acyl-amino-acids-elmiric-acids-endogenous-signaling-molecules-with-therapeutic-potential
#4
Sumner Burstein
The subject of N-acyl amino acid conjugates has been rapidly growing in recent years, especially with regard to their analgesic and anti-inflammatory actions. The field is comprised of a large family of lipid signaling molecules whose importance is only now being fully realized. The most widely studied member is N-arachidonoyl glycine (NAGly), which differs structurally from the endocannabinoid anandamide (N-arachidonoyl ethanolamide) by a single oxygen atom and the two are metabolically related. Topics that are covered in this mini review are: biosynthetic pathways for N-acyl amino acids, receptors for N-acyl amino acids, physiological actions of N-acyl amino acids, pharmacological effects of N-acyl amino acids and molecular mechanisms believed to be responsible for their effects...
November 14, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29113993/pxr-more-than-just-a-master-xenobiotic-receptor
#5
Peter Oladimeji, Taosheng Chen
Pregnane X receptor (PXR) is a nuclear receptor considered to be a master xenobiotic receptor that coordinately regulates the expression of genes encoding drug-metabolizing enzymes and drug transporters, to essentially detoxify and eliminate xenobiotics and endotoxins from the body. In the past several years, the function of PXR in the regulation of xenobiotic metabolism has been extensively studied, and the role of PXR as a xenobiotic sensor has been well-established. It is now clear, however, that PXR plays many other roles in addition to its xenobiotic sensing function...
November 7, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29097440/desensitization-and-tolerance-of-mu-opioid-receptors-on-pontine-kolliker-fuse-neurons
#6
Erica S Levitt, John T Williams
Acute desensitization of mu opioid receptors is thought to be an initial step in the development of tolerance to opioids. Given the resistance of the respiratory system to develop tolerance, desensitization of neurons in the Kölliker-Fuse (KF), a key area in the respiratory circuit, was examined. The activation of G protein-coupled inwardly rectifying potassium (GIRK) current was measured using whole-cell voltage-clamp recordings from KF and locus coeruleus (LC) neurons contained in acute rat brain slices...
November 2, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29093019/the-x-ray-crystal-structure-of-the-human-monooxygenase-cytochrome-p450-3a5-ritonavir-complex-reveals-active-site-differences-between-p450s-3a4-and-3a5
#7
Mei-Hui Hsu, Uzen Savas, Eric F Johnson
Contributions of cytochrome P450 3A5 to the metabolic clearance of marketed drugs is unclear, but is likely to augment the metabolism of several drugs that are largely cleared by P450 3A4. Selective metabolism by 3A4 is often a concern in drug development due to potential drug-drug interactions and the variability of 3A4 and 3A5 expression. The contribution of P450 3A5 to these clearance pathways varies between individuals due to genetic differences and similarities and differences in the metabolic properties of 3A5 compared to 3A4...
November 1, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29070696/structural-determinants-influencing-the-potency-and-selectivity-of-indazole-paroxetine-hybrid-g-protein-coupled-receptor-kinase-2-inhibitors
#8
Renee Bouley, Helen V Waldschmidt, M Claire Cato, Alessandro Cannavo, Jianliang Song, Joseph Y Cheung, Xin-Qiu Yao, Walter J Koch, Scott D Larsen, John J Tesmer
G protein-coupled receptor kinases (GRKs) phosphorylate activated receptors to promote arrestin binding, decoupling from heterotrimeric G proteins, and internalization. GRK2 and GRK5 are overexpressed in the failing heart and thus have become therapeutic targets. Previously, we discovered two classes of GRK2-selective inhibitors, one stemming from GSK180736A, a ROCK1 inhibitor, and the other from paroxetine, a selective serotonin-reuptake inhibitor. These two classes of compounds bind to the GRK2 active site in a similar configuration, but contain different hinge-binding "warheads": indazole and benzodioxole, respectively...
October 25, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29070695/relationship-between-dna-methylation-in-the-5-cpg-island-of-the-slc47a1-mate1-gene-and-inter-individual-variability-in-mate1-expression-in-the-human-liver
#9
Toshihiro Tanaka, Takeshi Hirota, Ichiro Ieiri
Multidrug and toxin extrusion protein 1 (MATE1), which is encoded by SLC47A1, mediates the excretion of organic cations into bile and urine. Some genetic variants in human MATE1 altered its transport function in in vitro experiments; however, differences in the pharmacokinetics of substrate drugs cannot be explained by genetic variations in humans. In the present study, we investigated whether DNA methylation was involved in inter-individual variability in MATE1 expression in the human liver. Approximately 20-fold inter-individual variability in MATE1 mRNA expression levels was observed in liver samples and mRNA expression levels negatively correlated with methylation levels of the CpG island in the 27 kb upstream of SLC47A1 DNA demethylation by a treatment with 5-aza-2'-deoxycytidine increased MATE1 mRNA expression in MATE1-negative cell lines...
October 25, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29051318/evaluation-of-the-selectivity-and-cysteine-dependence-of-inhibitors-across-the-regulator-of-g-protein-signaling-family
#10
Michael P Hayes, Christopher R Bodle, David L Roman
Since their discovery over 20 years ago, Regulators of G Protein Signaling (RGS) proteins have received considerable attention as potential drug targets due to their ability to modulate G α activity. Efforts to identify small molecules capable of inhibiting the protein-protein interaction between activated G α subunits and RGS proteins have yielded a substantial number of inhibitors, especially towards the well-studied RGS4. These efforts also identified that many of these small molecules inhibit the protein- protein interaction through covalent modification of Cysteine residues within the RGS domain that are located distal to the G α -binding interface...
October 19, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29038158/activation-of-human-transient-receptor-potential-melastatin-8-trpm8-by-calcium-rich-particulate-materials-and-effects-on-human-lung-cells
#11
John G Lamb, Erin G Romero, Zhenyu Lu, Seychelle K Marcus, Hannah C Peterson, John M Veranth, Cassandra E Deering-Rice, Christopher A Reilly
To better understand how adverse health effects are caused by particulate materials, and to develop preventative measures, it is important to identify the properties of particles and proteins that link exposure with specific biological outcomes. Coal fly ash (CFA) is a by-product of coal combustion that can affect human health. Here we show that human transient receptor potential melastatin-8 (TRPM8) and an N-terminally truncated TRPM8 variant (TRPM8-Δ801) are activated by CFA and calcium-rich nanoparticles and/or soluble salts within CFA...
October 16, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29030392/hydrogen-sulfide-preserves-enos-function-by-inhibiting-pyk2-implications-for-cardiomyocyte-survival-and-cardioprotection
#12
Sofia-Iris Bibli, Csaba Szabo, Athanasia Chatzianastasiou, Bert Luck, Sven Zukunft, Ingrid Fleming, Andreas Papapetropoulos
Hydrogen sulfide (H2S) exhibits beneficial effects in the cardiovascular system, many of which depend on nitric oxide (NO). Proline-rich tyrosine kinase 2 (PYK2), a redox-sensitive tyrosine kinase, directly phosphorylates and inhibits eNOS. Herein, we investigated the ability of H2S to relieve PYK2-mediated eNOS inhibition and evaluated the importance of the H2S/PYK2/eNOS axis on cardiomyocyte injury in vitro and in vivo. Exposure of H9c2 cardiomyocytes to H2O2 or pharmacological inhibition of H2S production increased PYK2 (Y402) and eNOS (Y656) phosphorylation...
October 13, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29025968/activation-of-ampk-mtorc1-mediated-autophagy-by-metformin-reverses-clk1-deficiency-sensitized-dopaminergic-neuronal-death
#13
Qiuting Yan, Chaojun Han, Guanghui Wang, John L Waddington, Longtai Zheng, Xuechu Zhen
The autophagy-lysosome pathway (ALP) plays a critical role in the pathology of Parkinson's disease (PD). Clk1 (coq7) is a mitochondrial hydroxylase that is essential for Coenzyme Q (ubiquinone) biosynthesis. We have reported previously that Clk1 regulates microglia activation via modulating microglia metabolic reprogramming, which contributes to dopaminergic neuronal survival. This study explored the direct effect of Clk1 on dopaminergic neuronal survival. We demonstrated that Clk1 deficiency inhibited dopaminergic neuronal autophagy in cultured MN9D dopaminergic neurons and in SNc of Clk+/- mutant mice and consequently sensitized dopaminergic neuron damage and behavioral defects...
October 12, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29025967/diminazene-is-a-slow-pore-blocker-of-acid-sensing-ion-channel-1a-asic1a
#14
Axel Schmidt, Giulia Rossetti, Sylvia Joussen, Stefan Grunder
Acid-sensing ion channels (ASICs) are neuronal receptors for extracellular protons. They contribute to the excitatory postsynaptic current and to the detection of painful acidosis. Moreover, they are activated during peripheral inflammation and acidosis associated with various neuronal disorders such as stroke and neuro-inflammation, rendering them interesting drug targets. Diminazene aceturate is a small molecule inhibitor of ASICs with a reported apparent affinity in the low micromolar range, making it an interesting lead compound...
October 12, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29025966/notch-signaling-linking-embryonic-lung-development-and-asthmatic-airway-remodeling
#15
Musaddique Hussain, Chengyun Xu, Mashaal Ahmad, Meiping Lu, Xiling Wu, Lanfang Tang, Ximei Wu
Lung development is mediated by assorted signaling proteins, and orchestrated by complex mesenchymal-epithelial interactions. Notch signaling is an evolutionarily conserved cell-cell communication mechanism that exhibits a pivotal role in lung development. Notably, both aberrant expression and loss of regulation of Notch signaling are critically linked to the pathogenesis of various lung diseases, in particular, pulmonary fibrosis, lung cancer, pulmonary arterial hypertension, and asthmatic airway remodeling; implying that precise regulation of intensity and duration of Notch signaling is imperative for appropriate lung development...
October 12, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28974538/rvx-297-a-bet-bromodomain-inhibitor-has-therapeutic-effects-in-preclinical-models-of-acute-inflammation-and-autoimmune-disease
#16
Ravi Jahagirdar, Sarah Attwell, Suzana Marusic, Alison Bendele, Narmada Shenoy, Kevin G McLure, Dean Gilham, Karen Norek, Henrik C Hansen, Raymond Yu, Jennifer Tobin, Gregory S Wagner, Peter R Young, Norman Cw Wong, Ewelina Kulikowski
Bromodomain and extra-terminal (BET) domain proteins are chromatin adapters that bind acetylated histone marks via two tandem bromodomains (BD1 and BD2) to regulate gene transcription. BET proteins are involved in transcriptional reprogramming in response to inflammatory stimuli. BET bromodomain inhibitors (BETi) that are non-selective for BD1 or BD2 have recognized anti-inflammatory properties in vitro and counter pathology in models of inflammation or autoimmune disease. While both BD1 and BD2 bind acetylated histone residues, they may independently regulate expression of BET sensitive genes...
September 29, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28954816/effective-attenuation-of-adenosine-a1r-signaling-by-neurabin-requires-oligomerization-of-neurabin
#17
Yunjia Chen, Christopher Booth, Hongxia Wang, Raymond Wang, Dimitra Terzi, Venetia Zachariou, Kai Jiao, Jin Zhang, Qin Wang
The adenosine A1 receptor (A1R) is a key mediator of the neuroprotective effect by endogenous adenosine. Yet, targeting this receptor for neuroprotection is challenging due to its broad expression throughout the body. A mechanistic understanding of the regulation of A1R signaling is necessary for the future design of therapeutic agents that can selectively enhance A1R-mediated responses in the nervous system. In the present study, we demonstrate that A1R activation leads to a sustained localization of RGS4 at the plasma membrane, a process that requires neurabin, a neural tissue-specific protein...
September 27, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29114084/correction-to-the-emerging-role-of-cable1-in-cancer-and-other-diseases
#18
(no author information available yet)
No abstract text is available yet for this article.
December 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29114083/correction-to-g-protein-coupled-receptor-kinase-2-as-a-potential-modulator-of-the-hallmarks-of-cancer
#19
(no author information available yet)
No abstract text is available yet for this article.
December 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29114082/correction-to-novel-small-molecule-jp-153-targets-the-src-fak-paxillin-signaling-complex-to-inhibit-vegf-induced-retinal-angiogenesis
#20
(no author information available yet)
No abstract text is available yet for this article.
December 2017: Molecular Pharmacology
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