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Molecular Pharmacology

Richard D Rainbow, Sean Brennan, Robert Jackson, Alison J Beech, Amal Bengreed, Helen V Waldschmidt, John Jg Tesmer, Ra John Challiss, Jonathon M Willets
Vasoconstrictor-driven G protein-coupled receptor (GPCR)/phospholipase C (PLC) signalling increases intracellular Ca2+ concentration to mediate arterial contraction. To counteract vasoconstrictor-induced contraction, GPCR/PLC signalling can be desensitized by G protein-coupled receptor kinases (GRKs), with GRK2 playing a predominant role in isolated arterial smooth muscle cells. Here, we utilize an array of GRK2 inhibitors to assess their effects on the desensitization of UTP and angiotensin II-mediated arterial contractions...
July 6, 2018: Molecular Pharmacology
Grace Woodruff, Christian G Bouwkamp, Femke M de Vrij, Timothy Lovenberg, Pascal Bonaventure, Steven A Kushner, Anthony W Harrington
Zinc homeostasis is a highly regulated process in mammalian cells that is critical for normal growth and development. Movement of zinc across cell compartments is controlled by two classes of transporters: Slc39a family members transport zinc into the cytosol from either the extracellular space or from intracellular stores such as the endoplasmic reticulum (ER), while the SSLC30A family mediates zinc efflux from the cytosol. Here we report that genetic ablation of SLC39A7 (ZIP7) results in decreased cytosolic zinc levels, increased ER zinc levels, impaired cell proliferation, and induction of ER stress...
July 6, 2018: Molecular Pharmacology
Yuchen Wang, Shiqi Tang, Kyle E Harvey, Amy E Salyer, T August Li, Emily K Rantz, Markus A Lill, Gregory H Hockerman
Nifedipine and FPL 64176 (FPL), which block and potentiate L-type voltage-gated Ca2+ channels respectively, more potently modulate Cav1.2 than Cav1.3. To identify potential strategies for developing subtype-selective inhibitors, we investigated the role of divergent amino acid residues in transmembrane domains IIIS5 and the extracellular IIIS5-3P loop region in modulation of these channels by nifedipine and FPL. Insertion of the extracellular IIIS5-3P loop from Cav1.2 into Cav1.3 (Cav1.3+) reduced the IC50 of nifedipine from 289 nM to 101 nM, and substitution of S1100 with an A residue, as in Cav1...
July 6, 2018: Molecular Pharmacology
Jihui Zhang, Jie Chen, Gary K Newton, Trevor R Perrior, Clive Robinson
Diverse evidence from epidemiological surveys and investigations into the molecular basis of allergenicity have revealed that a small cadre of 'initiator' allergens are responsible for promoting the development of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis. Pre-eminent among initiator allergens are those derived from house dust mites (HDM). In these mites, group 1 allergens function as cysteine peptidase digestive enzymes to which humans are exposed by inhalation of HDM fecal pellets...
July 5, 2018: Molecular Pharmacology
Kevin E Weigl, Gwenaelle Conseil, Alice J Rothnie, May Arama, Yossi Tsfadia, Susan P C Cole
The 190 kDa human MRP1 is an ATP-binding cassette multidrug and multiorganic anion efflux transporter. The 17 transmembrane helices of its three membrane spanning domains, together with its two nucleotide binding domains (NBDs), form a stabilizing network of domain-domain interactions that ensure substrate binding in the cytoplasm is efficiently coupled to ATP binding and hydrolysis to effect solute efflux into the extracellular milieu. Here we show that Ala substitution of Phe583 in an outward-facing loop between the two halves of the transporter essentially eliminated binding of multiple organic anions by MRP1...
July 5, 2018: Molecular Pharmacology
Christopher F Rider, Mohammed O Altonsy, Mahmoud M Mostafa, Suharsh V Shah, Sarah Sasse, Martijn L Manson, Dong Yan, Carina Karrman-Mardh, Anna Miller-Larsson, Anthony N Gerber, Mark A Giembycz, Robert Newton
In asthma, the clinical efficacy of inhaled corticosteroids (ICSs) is enhanced by long-acting β2 -adrenoceptor agonists (LABAs). ICSs, or more accurately, glucocorticoids, promote therapeutically-relevant changes in gene expression and, in primary human bronchial epithelial cells (pHBECs) and airway smooth muscle cells, this genomic effect can be enhanced by a LABA. Modelling this interaction in human bronchial airway epithelial BEAS-2B cells transfected with a 2×glucocorticoid response element (2×GRE)-driven luciferase reporter showed glucocorticoid-induced transcription to be enhanced 2- to 3-fold by LABA...
June 29, 2018: Molecular Pharmacology
Hiroaki Takesue, Takeshi Hirota, Mami Tachimura, Ayane Tokashiki, Ichiro Ieiri
Filtered glucose is mostly reabsorbed by sodium-glucose co-transporter 2 (SGLT2) in the proximal tubules. SGLT2 is predominantly expressed in the human kidney. However, the regulatory mechanisms for SGLT2 gene expression in the human kidney remain unclear. We herein elucidated the transcriptional regulatory mechanisms for the SGLT2 gene by nucleosome occupancy in the SGLT2 promoter region. Expressions of SGLT2 mRNA and protein were markedly weaker in human kidney-derived HK-2 cells than the human kidney. The nucleosome occupancy level in the SGLT2 promoter region was low in the kidney, but high in HK-2 cells...
June 29, 2018: Molecular Pharmacology
Dong Gui Hu, Julie-Ann Hulin, Dhilushi D Wijayakumara, Ross A McKinnon, Peter I Mackenzie, Robyn Meech
Recent studies have investigated alternative splicing profiles of UGT genes and identified over 130 different alternatively spliced UGT transcripts. Although UGT genes are highly clustered, the formation of chimeric transcripts by intergenic splicing between two or more UGT genes has not yet been reported. This study identified twelve chimeric transcripts (chimeras A-L) containing exons from two or three genes of the four neighbouring UGT genes (UGT2B15, UGT2B29P2, UGT2B17, and UGT2B29P1) in human liver and prostate cancer cells...
June 29, 2018: Molecular Pharmacology
Sara Bdioui, Julien Verdi, Nicolas Pierre, Eric Trinquet, Thomas Roux, Terry Kenakin
This paper discusses the process of determining the activity of candidate molecules targeting Gq-protein activation of GPCRs for possible therapeutic application with two functional assays; calcium release and inositol phosphate metabolism (IP1). While both are suitable for detecting ligand activity (screening), differences are seen when these assays are used to quantitatively measure ligand parameters for therapeutic activity. Specifically, responses for Gq-related pathways present different and dissimulating patterns depending on the functional assay used to assess them...
June 28, 2018: Molecular Pharmacology
Monica Soto-Velasquez, Michael P Hayes, Aktan Alpsoy, Emily C Dykhuizen, Val J Watts
Functional characterization of adenylyl cyclase (AC) isoforms has proven to be challenging in mammalian cells due to the endogenous expression of multiple AC isoforms, and the high background cyclic AMP (cAMP) levels induced by non-selective AC activators. To simplify the characterization of individual transmembrane AC (mAC) isoforms, we generated a HEK293 cell line with low cAMP levels by knocking out two highly expressed ACs, AC3 and AC6, using CRISPR/Cas9 technology. Stable HEK293 cell lines were generated lacking either AC6 (HEK-ACΔ6) or both AC3 and AC6 (HEK-ACΔ3/6)...
June 27, 2018: Molecular Pharmacology
Danica Jurcakova, Fei Ru, Marian Kollarik, Hui Sun, Jeffrey Krajewski, Bradley J Undem
We evaluated the effect of voltage-gated sodium channel 1 (NaV1) blockers in three non-overlapping C-fiber subtypes in the mouse skin: namely, chloroquine (CQ)-sensitive C-fibers with high mechanical thresholds - ostensibly itch C-fibers; secondly, CQ-insensitive, capsaicin-sensitive C-fibers with high mechanical thresholds - ostensibly nociceptors; and CQ and capsaicin-insensitive C-fibers with very low mechanical threshold - C-LTMs. NaV1 blocking drugs were applied to the nerve terminal receptive fields using an innervated isolated dorsal mouse skin-nerve preparation where the drugs are delivered into the skin intra-arterially...
June 25, 2018: Molecular Pharmacology
Yoshihiro Morishima, Ranjit K Mehta, Miyako Yoshimura, Miranda Lau, Daniel R Southworth, Theodore S Lawrence, William B Pratt, Mukesh K Nyati, Yoichi Osawa
Several hundred proteins cycle into heterocomplexes with a dimer of the chaperone Hsp90, regulating their activity and turnover. There are two isoforms of Hsp90, Hsp90α and Hsp90β, and their relative chaperone activities and composition in these client protein·Hsp90 heterocomplexes has not been determined. Here, we have examined the activity of human Hsp90α and Hsp90β in a purified five-protein chaperone machinery that assembles glucocorticoid receptor (GR)·Hsp90 heterocomplexes to generate high affinity steroid binding activity...
June 25, 2018: Molecular Pharmacology
Stephanie Chin, Maurita Hung, Amy Won, Yu-Sheng Wu, Saumel Ahmadi, Donghe Yang, Salma Elmallah, Krimo Toutah, C Michael Hamilton, Robert N Young, Russell D Viirre, Christopher M Yip, Christine E Bear
The major Cystic Fibrosis (CF) causing mutation, the deletion of phenylalanine at position 508 (F508del) at the cystic fibrosis transmembrane conductance regulator (CFTR), occurs in approximately 90% of the CF population. Recently, a combination therapy, comprising a corrector (VX-809) that rescues the processing defects of F508del-CFTR and a potentiator (VX-770) that rescues mutant channel activity, was approved for CF patients homozygous for this mutation. However, clinical studies revealed that the efficacy of this drug on lung function was modest and variable amongst patients...
June 14, 2018: Molecular Pharmacology
Sujay V Kharade, Haruto Kurata, Aaron Bender, Anna L Blobaum, Eric E Figueroa, Amanda M Duran, Meghan Kramer, Emily Days, Paige Vinson, Daniel Flores, Lisa M Satlin, Jens Meiler, C David Weaver, Craig W Lindsley, Corey R Hopkins, Jerod S Denton
The inward rectifier potassium (Kir) channel Kir4.1 (KCNJ10) carries out important physiological roles in epithelial cells of the kidney, astrocytes in the central nervous system, and stria vascularis of the inner ear. Loss-of-function mutations in KCNJ10 lead to EAST/SeSAME syndrome, which is characterized by epilepsy, ataxia, renal salt wasting, and sensorineural deafness. While genetic approaches have been indispensable for establishing the importance of Kir4.1 in the normal function of these tissues, the availability of pharmacological tools for acutely manipulating the activity of Kir4...
June 12, 2018: Molecular Pharmacology
Philip J Sandoval, Kimberely M Zorn, Alex M Clark, Sean Ekins, Stephen H Wright
The organic cation transporter OCT2 mediates the entry step for organic cation secretion by renal proximal tubule cells and is a site of unwanted drug-drug interactions (DDIs). But reliance on decision tree-based predictions of DDIs at OCT2 that depend on IC50 values can be suspect because they can be influenced by choice of transported substrate; for example, IC50 s for inhibition of metformin vs MPP transport can vary by 5 to 10-fold. However, it is not clear if substrate-dependence of ligand interaction is common among OCT2 substrates...
June 8, 2018: Molecular Pharmacology
Zhibo Gai, Michele Visentin, Ting Gui, Lin Zhao, Wolfgang E Thasler, Stephanie Hausler, Ivan Hartling, Alessio Cremonesi, Christian Hiller, Gerd A Kullak-Ublick
Inflammation has a recognized role in non-alcoholic fatty liver disease (NAFLD) progression. The present work studied the effect of high fat diet (HFD) on arachidonic acid metabolism in the liver and investigated the role of the farnesoid X receptor (FXR, NR1H4) in eicosanoid biosynthetic pathways and NF-kB signaling, major modulators of the inflammatory cascade. Mice were fed a HFD to induce NAFLD, then, treated with the FXR ligand obeticholic acid (OCA). Histology and gene expression analysis were performed on liver tissue...
May 9, 2018: Molecular Pharmacology
Philipp Y Maximov, Balkees Abderrahman, Sean W Fanning, Surojeet Sengupta, Ping Fan, Ramona F Curpan, Daniela Maria Quintana Rincon, Jeffery A Greenland, Shyamala S Rajan, Geoffrey L Greene, V Craig Jordan
Estrogen therapy was used to treat advanced breast cancer in postmenopausal women for decades until the introduction of tamoxifen. Resistance to long-term estrogen deprivation (LTED) with tamoxifen and aromatase inhibitors used as a treatment for breast cancer inevitably occurs, but unexpectedly low dose estrogen can cause regression of breast cancer and increase disease free survival in some patients. This therapeutic effect is attributed to estrogen-induced apoptosis in LTED breast cancer. Here we describe modulation of the estrogen receptor liganded with antiestrogens (endoxifen, 4-hydroxytamoxifen) and an estrogenic triphenylethylene (TPE) EthoxyTPE (EtOXTPE) on estrogen-induced apoptosis in LTED breast cancer cells...
May 8, 2018: Molecular Pharmacology
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August 2018: Molecular Pharmacology
Min Li, Ying Wu, Beiyan Zou, Xiaoliang Wang, Min Li, Haibo Yu
Sodium channels are important proteins in modulating neuronal membrane excitability. Genetic studies from patients and animals have indicated neuronal sodium channels play key roles in pain sensitization. We identified WB4101 (2-(2,6-Dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride), an antagonist of α1 -adrenoceptor, as a Nav1.7 inhibitor from a screen. The present study characterized the effects of WB4101 on sodium channels. We demonstrated that WB4101 inhibited both Nav1.7 and Nav1.8 channels with similar levels of potency...
August 2018: Molecular Pharmacology
Richard Oblad, Hayden Doughty, John Lawson, Merrill Christensen, Jason Kenealey
Combining chemotherapeutics to treat malignant tumors has been shown to be effective in preventing drug resistance, tumor recurrence, and reducing tumor size. We modeled combination drug therapy in PC-3 human prostate cancer cells using mixture design response surface methodology (MDRSM), a statistical technique designed to optimize compositions that we applied in a novel manner to design combinations of chemotherapeutics. Conventional chemotherapeutics (mitoxantrone, cabazitaxel, and docetaxel) and natural bioactive compounds (resveratrol, piperlongumine, and flavopiridol) were used in 12 different combinations containing three drugs at varying concentrations...
August 2018: Molecular Pharmacology
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