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Molecular Pharmacology

Seiji Sato, Xi-Ping Huang, Wes Kroeze, Bryan L Roth
In this study, we identified two previously described kinase inhibitors-- LY2784544 and GSK2636771-- as novel GPR39 agonists by unbiased small-molecule-based screening using a βarrestin recruitment screening approach (PRESTO-Tango). We characterized the signaling of LY2784544 and GSK2636771 and compared it with a previously described "GPR39-selective" agonist GPR39-C3 at both canonical and non-canonical signaling pathways. Unexpectedly, all three compounds displayed probe-dependent and pathway-dependent allosteric modulation by zinc...
October 17, 2016: Molecular Pharmacology
Marie-Laure Rives, Morena Shaw, Bin Zhu, Simon A Hinke, Alan Wickenden
In the liver, citrate is a key metabolic intermediate involved in the regulation of glycolysis and lipid synthesis and reduced expression of the hepatic citrate SLC13A5 transporter has been shown to improve metabolic outcomes in various animal models. Although inhibition of hepatic extracellular citrate uptake through SLC13A5 has been suggested as a potential therapeutic approach for Type-2 diabetes and/or fatty liver disease, so far, only a few SLC13A5 inhibitors have been identified. Moreover, their mechanism of action still remains unclear, potentially limiting their utility for in vivo proof-of-concept studies...
October 17, 2016: Molecular Pharmacology
Hannah E Majeski, Jing Yang
Past decades of cancer research have mainly focused on the role of various extracellular and intracellular biochemical signals on cancer progression and metastasis. Recent studies suggest an important role of mechanical forces in regulating cellular behaviors. This review first provides an overview of the mechanobiology research field. Then we specially focus on mechanotransduction pathways in cancer progression and describe in detail the key signaling components of such mechanotransduction pathways and ECM components that are altered in cancer...
October 14, 2016: Molecular Pharmacology
Anh Tn Nguyen, Jo-Anne Baltos, Trayder Thomas, Toan D Nguyen, Laura Lopez Munoz, Karen J Gregory, Paul J White, Patrick M Sexton, Arthur Christopoulos, Lauren T May
The adenosine A1 G protein-coupled receptor (A1AR) is an important therapeutic target implicated in a wide range of cardiovascular and neuronal disorders. Although it is well established that the A1AR orthosteric site is located within the receptor's transmembrane (TM) bundle, prior studies have implicated extracellular loop 2 (ECL2) as having a significant role in contributing to orthosteric ligand affinity and signaling for various G protein-coupled receptors (GPCRs). We thus performed extensive alanine scanning mutagenesis of the A1AR-ECL2 to explore the role of this domain on A1AR orthosteric ligand pharmacology...
September 28, 2016: Molecular Pharmacology
Anh Tn Nguyen, Elizabeth A Vecchio, Trayder Thomas, Toan D Nguyen, Luigi Aurelio, Peter J Scammells, Paul J White, Patrick M Sexton, Karen J Gregory, Lauren T May, Arthur Christopoulos
Allosteric modulation of adenosine A1 receptors (A1ARs) offers a novel therapeutic approach for the treatment of numerous central and peripheral disorders. However, despite decades of research, there is a relative paucity of structural information regarding the A1AR allosteric site and mechanisms governing cooperativity with orthosteric ligands. We combined alanine-scanning mutagenesis of the A1AR second extracellular loop (ECL2) with radioligand binding and functional interaction assays to quantify effects on allosteric ligand affinity, cooperativity and efficacy...
September 28, 2016: Molecular Pharmacology
Ana M Pajor, Cesar A de Oliveira, Kun Song, Kim Huard, Veerabahu Shanmugasundaram, Derek M Erion
The Na+/citrate transporter, NaCT (SLC13A5), is a therapeutic target for metabolic diseases. Citrate is an important signaling molecule that regulates the activity of lipid and glucose metabolizing enzymes in cells. Previous studies identified two compounds (2 and 4) that inhibit human NaCT with high affinity, and one of the compounds demonstrated specificity relative to other SLC13 family members. Here we use molecular modeling of hNaCT and site-directed mutagenesis followed by transport characterization and cell surface biotinylation to examine the residues involved in inhibitor binding and transport...
September 28, 2016: Molecular Pharmacology
Riley Edward Perszyk, John O DiRaddo, Katie L Strong, Chian-Ming Low, Kevin K Ogden, Alpa Khatri, Geoffrey A Vargish, Kenneth A Pelkey, Ludovic Tricoire, Dennis C Liotta, Yoland Smith, Chris J McBain, Stephen F Traynelis
NMDA receptors (NMDARs) are ionotropic glutamatergic receptors that have been implicated in learning, development, and neuropathological conditions. They are typically composed of GluN1 and GluN2A-D subunits. Whereas a great deal is known about the role of GluN2A- and GluN2B-containing NMDARs, much less is known about GluN2D-containing NMDARs. Here we explore the subunit composition of synaptic NMDARs on hippocampal interneurons. GluN2D mRNA was detected by single-cell PCR and in situ hybridization in diverse interneuron subtypes in the CA1 region of the hippocampus...
September 13, 2016: Molecular Pharmacology
Julia M Houthuijzen
Increased energy intake can lead to obesity, which increases the risk for the development of diabetes and cancer. Free fatty acids regulate numerous cellular processes like insulin secretion, inflammation, proliferation and cell migration. Dysregulation of these cellular functions by increased lipid intake plays a significant role in the development of diseases like diabetes and cancer. FFAR1 and FFAR4 are two free fatty acid receptors that are under increasing investigation for their roles in diabetes and more recently also cancer...
August 31, 2016: Molecular Pharmacology
André S Pupo, J Adolfo García-Sáinz
G protein-coupled receptors are sensors that interact with a large variety of elements, including photons, ions, and large proteins. Not surprisingly, these receptors participate in the numerous normal physiologic processes that we refer to as health and in its perturbations that constitute disease. It has been estimated that a large percentage of drugs currently used in therapeutics target these proteins, and this percentage is larger when illegal drugs are included. The state of the art in this field can be defined with the oxymoron "constant change," and enormous progress has been made in recent years...
November 2016: Molecular Pharmacology
José Vázquez-Prado, Ismael Bracho-Valdés, Rodolfo Daniel Cervantes-Villagrana, Guadalupe Reyes-Cruz
Cancer cells and stroma cells in tumors secrete chemotactic agonists that exacerbate invasive behavior, promote tumor-induced angiogenesis, and recruit protumoral bone marrow-derived cells. In response to shallow gradients of chemotactic stimuli recognized by G protein-coupled receptors (GPCRs), Gβγ-dependent signaling cascades contribute to specifying the spatiotemporal assembly of cytoskeletal structures that can dynamically alter cell morphology. This sophisticated process is intrinsically linked to the activation of Rho GTPases and their cytoskeletal-remodeling effectors...
November 2016: Molecular Pharmacology
Claudio M Costa-Neto, Lucas T Parreiras-E-Silva, Michel Bouvier
When studying G protein-coupled receptor (GPCR) signaling and ligand-biased agonism, at least three dimensional spaces must be considered, as follows: 1) the distinct conformations that can be stabilized by different ligands promoting the engagement of different signaling effectors and accessory regulators; 2) the distinct subcellular trafficking that can be conferred by different ligands, which results in spatially distinct signals; and 3) the differential binding kinetics that maintain the receptor in specific conformation and/or subcellular localization for different periods of time, allowing for the engagement of distinct signaling effector subsets...
November 2016: Molecular Pharmacology
Federico Monczor, Natalia Fernandez
H1 and H2 histamine receptor antagonists, although developed many decades ago, are still effective for the treatment of allergic and gastric acid-related conditions. This article focuses on novel aspects of the pharmacology and molecular mechanisms of histamine receptors that should be contemplated for optimizing current therapies, repositioning histaminergic ligands for new therapeutic uses, or even including agonists of the histaminergic system in the treatment of different pathologies such as leukemia or neurodegenerative disorders...
November 2016: Molecular Pharmacology
Marika Cordaro, Daniela Impellizzeri, Enrico Gugliandolo, Rosalba Siracusa, Rosalia Crupi, Emanuela Esposito, Salvatore Cuzzocrea
Leukocyte infiltration, improved levels of intercellular adhesion molecule 1 (ICAM-1), and oxidative stress in the colon are the principal factors in inflammatory bowel disease. The goal of the current study was to explore the effects of adelmidrol, an analog of the anti-inflammatory fatty acid amide signaling molecule palmitoylethanolamide, in mice subjected to experimental colitis. Additionally, to clarify whether the protective action of adelmidrol is dependent on the activation of peroxisome proliferator-activated receptors (PPARs), we investigated the effects of a PPARγ antagonist, GW9662, on adelmidrol action...
November 2016: Molecular Pharmacology
Paula G Slater, Hector E Yarur, Katia Gysling
The corticotropin-releasing factor (CRF) system, which is involved in stress, addiction, and anxiety disorders such as depression, acts through G-protein-coupled receptors (GPCRs) known as type-1 and type-2 CRF receptors. The purpose of this review is to highlight recent advances in the interactions of CRF receptors with other GPCRs and non-GPCR proteins and their associated functional consequences. A better understanding of these interactions may generate new pharmacological alternatives for the treatment of addiction and stress-related disorders...
November 2016: Molecular Pharmacology
Maíra H Nagai, Lucia Maria Armelin-Correa, Bettina Malnic
Odorant receptors (ORs) belong to a large gene family of rhodopsin-like G protein-coupled receptors (GPCRs). The mouse OR gene family is composed of ∼1000 OR genes, and the human OR gene family is composed of ∼400 OR genes. The OR genes are spread throughout the genome, and can be found in clusters or as solitary genes in almost all chromosomes. These chemosensory GPCRs are expressed in highly specialized cells, the olfactory sensory neurons of the nose. Each one of these neurons expresses a single OR gene out of the complete repertoire of genes...
November 2016: Molecular Pharmacology
Jonathan W Theile, Matthew D Fuller, Mark L Chapman
Voltage-gated sodium (Nav) channel inhibitors are used clinically as analgesics and local anesthetics. However, the absence of Nav channel isoform selectivity of current treatment options can result in adverse cardiac and central nervous system side effects, limiting their therapeutic utility. Human hereditary gain- or loss-of-pain disorders have demonstrated an essential role of Nav1.7 sodium channels in the sensation of pain, thus making this channel an attractive target for new pain therapies. We previously identified a novel, state-dependent human Nav1...
November 2016: Molecular Pharmacology
Olga Novikov, Zhongyan Wang, Elizabeth A Stanford, Ashley J Parks, Alejandra Ramirez-Cardenas, Esther Landesman, Israa Laklouk, Carmen Sarita-Reyes, Daniel Gusenleitner, Amy Li, Stefano Monti, Sara Manteiga, Kyongbum Lee, David H Sherr
The endogenous ligand-activated aryl hydrocarbon receptor (AHR) plays an important role in numerous biologic processes. As the known number of AHR-mediated processes grows, so too does the importance of determining what endogenous AHR ligands are produced, how their production is regulated, and what biologic consequences ensue. Consequently, our studies were designed primarily to determine whether ER(-)/PR(-)/Her2(-) breast cancer cells have the potential to produce endogenous AHR ligands and, if so, how production of these ligands is controlled...
November 2016: Molecular Pharmacology
Jung Seok Hwang, Sun Ah Ham, Taesik Yoo, Won Jin Lee, Kyung Shin Paek, Chi-Ho Lee, Han Geuk Seo
Peroxisome proliferator-activated receptor δ (PPARδ) has been implicated in vascular pathophysiology. However, its functions in atherogenic changes of the vascular wall have not been fully elucidated. PPARδ activated by GW501516 (2-[2-methyl-4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methylsulfanyl]phenoxy]acetic acid) significantly inhibited the migration and proliferation of vascular smooth muscle cells (VSMCs) triggered by oxidized low-density lipoprotein (oxLDL). These GW501516-mediated effects were significantly reversed by PPARδ-targeting small-interfering RNA (siRNA), indicating that PPARδ is involved in the action of GW501516...
November 2016: Molecular Pharmacology
Hyejin Yang, Junsung Woo, Ae Nim Pae, Min Young Um, Nam-Chul Cho, Ki Duk Park, Minseok Yoon, Jiyoung Kim, C Justin Lee, Suengmok Cho
α-Pinene is a major monoterpene of the pine tree essential oils. It has been reported that α-pinene shows anxiolytic and hypnotic effects upon inhaled administration. However, hypnotic effect by oral supplementation and the molecular mechanism of α-pinene have not been determined yet. By combining in vivo sleep behavior, ex vivo electrophysiological recording from brain slices, and in silico molecular modeling, we demonstrate that (-)-α-pinene shows sleep enhancing property through a direct binding to GABAA-benzodiazepine (BZD) receptors by acting as a partial modulator at the BZD binding site...
November 2016: Molecular Pharmacology
Sarah Dubaisi, Hailin Fang, Thomas A Kocarek, Melissa Runge-Morris
Cytosolic sulfotransferase 1C3 (SULT1C3) is the least characterized of the three human SULT1C subfamily members. Originally identified as an orphan SULT by computational analysis of the human genome, we recently reported that SULT1C3 is expressed in human intestine and LS180 colorectal adenocarcinoma cells and is upregulated by agonists of peroxisome proliferator-activated receptor (PPAR) α and γ To determine the mechanism responsible for PPAR-mediated upregulation, we prepared reporter plasmids containing fragments of the SULT1C3 5'-flanking region...
November 2016: Molecular Pharmacology
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