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CRISPR/Cas9 Genome Editing of the Human Topoisomerase IIαIntron 19 5′ Splice Site Circumvents Etoposide Resistance in Human Leukemia K562 Cells Mol. Pharmacol. (IF 3.664) Pub Date : 2021-03-01 Victor A. Hernandez; Jessika Carvajal-Moreno; Jonathan L. Papa; Nicholas Shkolnikov; Junan Li; Hatice Gulcin Ozer; Jack C. Yalowich; Terry S. Elton
An essential function of DNA topoisomerase IIα (TOP2α; 170 kDa, TOP2α/170) is to resolve DNA topologic entanglements during chromosome disjunction by introducing transient DNA double-stranded breaks. TOP2α/170 is an important target for DNA damage-stabilizing anticancer drugs, whose clinical efficacy is compromised by drug resistance often associated with decreased TOP2α/170 expression. We recently
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Biased Effect of Cardiotonic Steroids on Na/K-ATPase–Mediated Signal Transduction Mol. Pharmacol. (IF 3.664) Pub Date : 2021-03-01 Yunhui Xu; Pauline Marck; Minqi Huang; Jeffrey X. Xie; Tong Wang; Joseph I. Shapiro; Liquan Cai; Feng Feng; Zijian Xie
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Positive allosteric modulators of metabotropic glutamate receptor 5 as tool compounds to study signaling bias Mol. Pharmacol. (IF 3.664) Pub Date : 2021-02-18 Angela Arsova; Thor C. Møller; Shane D. Hellyer; Line Vedel; Simon R. Foster; Jakob L. Hansen; Hans Bräuner-Osborne; Karen J. Gregory
Positive allosteric modulation of metabotropic glutamate type 5 (mGlu5) receptor has emerged as a potential new therapeutic strategy for the treatment of schizophrenia and cognitive impairments. However, positive allosteric modulator (PAM) agonist activity has been associated with adverse side effects, and neurotoxicity has also been observed for pure PAMs. The structural and pharmacological basis
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Transcriptome-Level Interactions between Budesonide and Formoterol Provide Insight into the Mechanism of Action of Inhaled Corticosteroid/Long-Actingβ2-Adrenoceptor Agonist Combination Therapy in Asthma Mol. Pharmacol. (IF 3.664) Pub Date : 2021-03-01 Mahmoud M. Mostafa; Christopher F. Rider; N. Dulmini Wathugala; Richard Leigh; Mark A. Giembycz; Robert Newton
In 2019, the Global Initiative for Asthma treatment guidelines were updated to recommend that inhaled corticosteroid (ICS)/long-acting β2-adrenoceptor agonist (LABA) combination therapy should be a first-in-line treatment option for asthma. Although clinically superior to ICS, mechanisms underlying the efficacy of this combination therapy remain unclear. We hypothesized the existence of transcriptomic
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Elevated cAMP protects against diclofenac-induced toxicity in primary rat hepatocytes: a protective effect mediated by EPACs Mol. Pharmacol. (IF 3.664) Pub Date : 2021-02-11 Fabio Alejandro Aguilar Mora; Nshunge Musheshe; Asmaa Oun; Manon Buist-Homan; Frank Lezoualc'h; Xiaodong Cheng; Martina Schmidt; Han Moshage
Background: Chronic consumption of the nonsteroidal anti-inflammatory drug diclofenac may induce drug-induced liver injury (DILI). The mechanism of diclofenac-induced liver injury is partially elucidated and involves mitochondrial damage. Elevated cAMP protects hepatocytes against bile acid-induced injury. However, it is unknown whether cAMP protects against DILI and, if so, which downstream targets
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Title: Phosphoproteomic Analysis as an Approach for Understanding Molecular Mechanisms of cAMP-dependent Actions Mol. Pharmacol. (IF 3.664) Pub Date : 2021-02-11 Joseph A. Beavo; Martin Golkowski; Masami Shimizu-Albergine; Michael-Claude Beltejar; Karin E. Bornfeldt; Shao-En Ong
In recent years, highly sensitive mass spectrometry-based phosphoproteomic analysis is beginning to be applied to identification of protein kinase substrates altered downstream of increased cyclic 3',5'adenosine monophosphate (cAMP). Such studies identify a very large number of phosphorylation sites regulated in response to increased cAMP. Therefore, we now are tasked with the challenge of determining
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Nelfinavir and Its Active Metabolite M8 Are Partial Agonists and Competitive Antagonists of the Human Pregnane X Receptor Mol. Pharmacol. (IF 3.664) Pub Date : 2021-03-01 Oliver Burk; Thales Kronenberger; Oliver Keminer; Serene M. L. Lee; Tobias S. Schiergens; Matthias Schwab; Björn Windshügel
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Short-Term Acyl-CoA:Cholesterol Acyltransferase Inhibition, Combined with Apoprotein A1 Overexpression, Promotes Atherosclerosis Inflammation Resolution in Mice Mol. Pharmacol. (IF 3.664) Pub Date : 2021-03-01 Jaume Amengual; Yoscar Ogando; Cyrus Nikain; Alexandra Quezada; Kun Qian; Tomas Vaisar; Edward A. Fisher
Acyl-CoA:cholesterol acyltransferase (ACAT) mediates cellular cholesterol esterification. In atherosclerotic plaque macrophages, ACAT promotes cholesteryl ester accumulation, resulting in foam cell formation and atherosclerosis progression. Its complete inactivation in mice, however, showed toxic effects because of an excess of free cholesterol (FC) in macrophages, which can cause endoplasmic reticulum
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The Emerging Role of Neuronal Organoid Models in Drug Discovery: Potential Applications and Hurdles to Implementation Mol. Pharmacol. (IF 3.664) Pub Date : 2021-02-05 Laura A Struzyna; Marla L Watt
The high failure rate of drugs in the clinical pipeline is likely, in part, the result of inadequate preclinical models, particularly those for neurological disorders and neurodegenerative disease. Such preclinical animal models often suffer from fundamental species differences and rarely recapitulate all facets of neurological conditions, while conventional two-dimensional (2D) in vitro models fail
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Chronic exposure to SCO-267,an allosteric GPR40 full agonist, is effective in improving glycemic control in rats Mol. Pharmacol. (IF 3.664) Pub Date : 2021-02-05 Ryokichi Koyama; Mitsugi Ookawara; Masanori Watanabe; Yusuke Moritoh
Full agonist-mediated activation of free fatty acid receptor 1 (FFAR1/GPR40) alleviates diabetes in rodents. Considering that diabetes is a chronic disease, assessment of treatment durability of chronic exposure to a GPR40 full agonist is pivotal for treating patients with diabetes. However, the physiological significance of chronic in vitro and in vivo exposure to GPR40 full agonists is largely unclear
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Arrestin-dependent and -independent internalization of GPCRs - methods, mechanisms and implications on cell signaling Mol. Pharmacol. (IF 3.664) Pub Date : 2021-01-20 Ee Von Moo; Jeffrey R. van Senten; Hans Bräuner-Osborne; Thor C. Møller
Agonist-induced endocytosis is a key regulatory mechanism for controlling the responsiveness of the cell by changing the density of cell surface receptors. In addition to the role of endocytosis in signal termination, endocytosed G protein-coupled receptors (GPCRs) have been found to signal from intracellular compartments of the cell. Arrestins are generally believed to be the master regulators of
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Insights into the Structure-Activity Relationship of Glycosides as Positive Allosteric Modulators Acting on P2X7 Receptors Mol. Pharmacol. (IF 3.664) Pub Date : 2021-02-01 Waraporn Piyasirananda; Andrew Beekman; A. Ganesan; Stefan Bidula; Leanne Stokes
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Predicting Drug Interactions with Human Equilibrative Nucleoside Transporters 1 and 2 Using Functional Knockout Cell Lines and Bayesian Modeling Mol. Pharmacol. (IF 3.664) Pub Date : 2021-02-01 Siennah R. Miller; Xiaohong Zhang; Raymond K. Hau; Joseph L. Jilek; Erin Q. Jennings; James J. Galligan; Daniel H. Foil; Kimberley M. Zorn; Sean Ekins; Stephen H. Wright; Nathan J. Cherrington
Equilibrative nucleoside transporters (ENTs) 1 and 2 facilitate nucleoside transport across the blood-testis barrier (BTB). Improving drug entry into the testes with drugs that use endogenous transport pathways may lead to more effective treatments for diseases within the reproductive tract. In this study, CRISPR/CRISPR-associated protein 9 was used to generate HeLa cell lines in which ENT expression
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GABAAReceptors Expressed in Oligodendrocytes Cultured from the Neonatal Rat Containα3 andγ1 Subunits and Present Differential Functional and Pharmacological Properties Mol. Pharmacol. (IF 3.664) Pub Date : 2021-02-01 Rainald Pablo Ordaz; Edith Garay; Agenor Limon; Alberto Pérez-Samartín; María Victoria Sánchez-Gómez; Leticia Robles-Martínez; Abraham Cisneros-Mejorado; Carlos Matute; Rogelio O. Arellano
Oligodendrocytes (OLs) express functional GABAA receptors (GABAARs) that are activated by GABA released at synaptic contacts with axons or by ambient GABA in extrasynaptic domains. In both instances, the receptors’ molecular identity has not been fully defined. Furthermore, data on their structural diversity in different brain regions and information on age-dependent changes in their molecular composition
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Mechanism-based Inactivation of Cytochrome P450 3A4 by Benzbromarone Mol. Pharmacol. (IF 3.664) Pub Date : 2021-01-12 Lloyd Wei Tat Tang; Ravi Kumar Verma; Hao Fan; Eric Chun Yong Chan
Benzbromarone (BBR), a potent uricosuric agent for the management of gout, is known to cause fatal fulminant hepatitis. While the mechanism of BBR-induced idiosyncratic hepatotoxicity remains unelucidated, cytochrome P450 enzyme (CYP450)-mediated bioactivation of BBR to electrophilic reactive metabolites is commonly regarded as a key molecular-initiating event. However, apart from causing aberrant
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A potential role for SerpinA3N in acetaminophen-induced hepatotoxicity Mol. Pharmacol. (IF 3.664) Pub Date : 2021-01-12 Melanie Tran; Jianguo Wu; Li Wang; Dong-Ju Shin
Acetaminophen (APAP) is a commonly used pain and fever reliver but is also the most frequent cause of drug induced liver injury. The mechanism pertaining acetaminophen toxicity has been well documented, while mechanisms of hepatotoxicity are not well established. Serine (or cysteine) peptidase inhibitor, clade A, member 3N (SerpinA3N), a serine protease inhibitor, is synthesized in the liver but the
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Molecular Mechanisms for the Inflammation-Resolving Actions of Lenabasum Mol. Pharmacol. (IF 3.664) Pub Date : 2021-02-01 Sumner Burstein
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Identification and Characterization of a Novel Large-Conductance Calcium-Activated Potassium Channel Activator, CTIBD, and Its Relaxation Effect on Urinary Bladder Smooth Muscle Mol. Pharmacol. (IF 3.664) Pub Date : 2021-02-01 Narasaem Lee; Bong Hee Lim; Kyu-Sung Lee; Jimin Shin; Haushabhau S. Pagire; Suvarna H. Pagire; Jin Hee Ahn; Sung Won Lee; Tong Mook Kang; Chul-Seung Park
The large-conductance calcium-activated potassium channel (BKCa channel) is expressed on various tissues and is involved in smooth muscle relaxation. The channel is highly expressed on urinary bladder smooth muscle cells and regulates the repolarization phase of the spontaneous action potentials that control muscle contraction. To discover novel chemical activators of the BKCa channel, we screened
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Distinct Regulation of Cardiac Fibroblast Proliferation and Transdifferentiation by Classical and Novel Protein Kinase C Isoforms: Possible Implications for New Antifibrotic Therapies Mol. Pharmacol. (IF 3.664) Pub Date : 2021-02-01 S. Tuuli Karhu; Heikki Ruskoaho; Virpi Talman
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Macrophage-Inducible C-Type Lectin Signaling Exacerbates Acetaminophen-Induced Liver Injury by Promoting Kupffer Cell Activation in Mice Mol. Pharmacol. (IF 3.664) Pub Date : 2021-02-01 Jing Zhao; Jong-Won Kim; Zixiong Zhou; Jing Qi; Weishun Tian; Chae Woong Lim; Kang Min Han; Bumseok Kim
Overdose of acetaminophen (APAP) has become one of the most frequent causes of acute liver failure. Macrophage-inducible C-type lectin (Mincle) acts as a key moderator in immune responses by recognizing spliceosome-associated protein 130 (SAP130), which is an endogenous ligand released by necrotic cells. This study aims to explore the function of Mincle in APAP-induced hepatotoxicity. Wild-type (WT)
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Proteomic approaches to investigate regulated trafficking and signaling of GPCRs Mol. Pharmacol. (IF 3.664) Pub Date : 2020-12-22 Mark von Zastrow
Advances in proteomic methodologies based on quantitative mass spectrometry are now transforming pharmacology and experimental biology more broadly. The present review will discuss several examples, based on work in the author's laboratory that focuses on delineating relationships between GPCR signaling and trafficking in the endocytic network. The examples highlighted correspond to those discussed
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Identification of the Functional Binding Site for the Convulsant Tetramethylenedisulfotetramine in the Pore of theα2β3γ2GABAAReceptor Mol. Pharmacol. (IF 3.664) Pub Date : 2021-01-01 Brandon Pressly; Ruth D. Lee; Bogdan Barnych; Bruce D. Hammock; Heike Wulff
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Protective Effects of Flavonoids in Acute Models of Light-Induced Retinal Degeneration Mol. Pharmacol. (IF 3.664) Pub Date : 2021-01-01 Joseph T. Ortega; Tanu Parmar; Marcin Golczak; Beata Jastrzebska
Degeneration of photoreceptors caused by excessive illumination, inherited mutations, or aging is the principal pathology of blinding diseases. Pharmacological compounds that stabilize the visual receptor rhodopsin and modulate the cellular pathways triggering death of photoreceptors could avert this pathology. Interestingly, flavonoids can modulate the cellular processes, such as oxidative stress
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Characterization of Vixotrigine, a Broad-Spectrum Voltage-Gated Sodium Channel Blocker Mol. Pharmacol. (IF 3.664) Pub Date : 2021-01-01 Christopher A Hinckley; Yuri Kuryshev; Alissende Sers; Alexander Barre; Bruno Buisson; Himanshu Naik; Mihaly Hajos
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A Benzodiazepine Ligand with Improved GABAAReceptorα5-Subunit Selectivity Driven by Interactions with Loop C Mol. Pharmacol. (IF 3.664) Pub Date : 2021-01-01 Xenia Simeone; Filip Koniuszewski; Markus Müllegger; Andreas Smetka; Friederike Steudle; Roshan Puthenkalam; Margot Ernst; Petra Scholze
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Targeting ACE2/Angiotensin-(1-7)/Mas Receptor Axis in the Vascular Progenitor Cells for Cardiovascular Diseases. Mol. Pharmacol. (IF 3.664) Pub Date : 2021-01-01 Yagna Pr Jarajapu
Bone marrow–derived hematopoietic stem/progenitor cells are vasculogenic and play an important role in endothelial health and vascular homeostasis by participating in postnatal vasculogenesis. Progenitor cells are mobilized from bone marrow niches in response to remote ischemic injury and migrate to the areas of damage and stimulate revascularization largely by paracrine activation of angiogenic functions
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Dysregulation of Angiotensin Converting Enzyme 2 Expression and Function in Comorbid Disease Conditions Possibly Contributes to Coronavirus Infectious Disease 2019 Complication Severity Mol. Pharmacol. (IF 3.664) Pub Date : 2021-01-01 Safaa H Hammoud; Zena Wehbe; Samar Abdelhady; Firas Kobeissy; Ali H. Eid; Ahmed F. El-Yazbi
ACE2 has emerged as a double agent in the COVID-19 ordeal, as it is both physiologically protective and virally conducive. The identification of ACE2 in as many as 72 tissues suggests that extrapulmonary invasion and damage is likely, which indeed has already been demonstrated by cardiovascular and gastrointestinal symptoms. On the other hand, identifying ACE2 dysregulation in patients with comorbidities
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Berberine Repressesβ-Catenin Translation Involving 4E-BPs in Hepatocellular Carcinoma Cells Mol. Pharmacol. (IF 3.664) Pub Date : 2021-01-01 Kanchan Vishnoi; Rong Ke; Karan S. Saini; Navin Viswakarma; Rakesh Sathish Nair; Subhasis Das; Zhengjia Chen; Ajay Rana; Basabi Rana
Aberrant activation of Wnt/β-catenin axis occurs in several gastrointestinal malignancies due to inactivating mutations of adenomatous polyposis coli (in colorectal cancer) or activating mutations of β-catenin itself [in hepatocellular carcinoma (HCC)]. These lead to β-catenin stabilization, increase in β-catenin/T-cell factor (TCF)–mediated transcriptional activation, and target gene expression, many
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Domain-Swap Dimerization ofAcanthamoeba castellaniiCYP51 and a Unique Mechanism of Inactivation by Isavuconazole Mol. Pharmacol. (IF 3.664) Pub Date : 2020-12-01 Vandna Sharma; Brian Shing; Lilian Hernandez-Alvarez; Anjan Debnath; Larissa M. Podust
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Reduced Activation of the Synaptic-Type GABAAReceptor Following Prolonged Exposure to Low Concentrations of Agonists: Relationship between Tonic Activity and Desensitization Mol. Pharmacol. (IF 3.664) Pub Date : 2020-12-01 Spencer R. Pierce; Allison L. Germann; Alex S. Evers; Joe Henry Steinbach; Gustav Akk
Synaptic GABAA receptors are alternately exposed to short pulses of a high, millimolar concentration of GABA and prolonged periods of low, micromolar concentration of the transmitter. Prior work has indicated that exposure to micromolar concentrations of GABA can both activate the postsynaptic receptors generating sustained low-amplitude current and desensitize the receptors, thereby reducing the peak
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Emerging roles for Regulator of G Protein Signaling 2 in (patho)physiology. Mol. Pharmacol. (IF 3.664) Pub Date : 2020-12-01 Harrison J McNabb,Qian Zhang,Benita Sjögren
Since their discovery in the mid-1990s, regulator of G protein signaling (RGS) proteins have emerged as key regulators of signaling through G protein–coupled receptors. Among the over 20 known RGS proteins, RGS2 has received increasing interest as a potential therapeutic drug target with broad clinical implications. RGS2 is a member of the R4 subfamily of RGS proteins and is unique in that it is selective
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Regulators of G protein signaling in analgesia and addiction. Mol. Pharmacol. (IF 3.664) Pub Date : 2020-12-01 Farhana Sakloth,Claire Polizu,Feodora Bertherat,Venetia Zachariou
Regulator of G protein signaling (RGS) proteins are multifunctional proteins expressed in peripheral and neuronal cells, playing critical roles in development, physiologic processes, and pharmacological responses. RGS proteins primarily act as GTPase accelerators for activated Gα subunits of G-protein coupled receptors, but they may also modulate signal transduction by several other mechanisms. Over
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RGS proteins as critical regulators of motor function and their implications in Parkinson's disease. Mol. Pharmacol. (IF 3.664) Pub Date : 2020-12-01 Katelin E Ahlers-Dannen,Mackenzie M Spicer,Rory A Fisher
Parkinson disease (PD) is a devastating, largely nonfamilial, age-related disorder caused by the progressive loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Release of DA from these neurons into the dorsal striatum is crucial for regulating movement and their loss causes PD. Unfortunately, the mechanisms underlying SNc neurodegeneration remain unclear, and currently there
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Glutamate,d-(−)-2-Amino-5-Phosphonopentanoic Acid, andN-Methyl-d-Aspartate Do Not Directly Modulate Glycine Receptors Mol. Pharmacol. (IF 3.664) Pub Date : 2020-12-01 Karin R. Aubrey; Diba Sheipouri; Thomas Balle; Robert J. Vandenberg; Yo Otsu
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Arginine-259 of UGT2B7 Confers UDP-Sugar Selectivity Mol. Pharmacol. (IF 3.664) Pub Date : 2020-12-01 Pramod C. Nair; Nuy Chau; Ross A. McKinnon; John O. Miners
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Allosterically Potentiatedα7 Nicotinic Acetylcholine Receptors: Reduced Calcium Permeability and Current-Independent Control of Intracellular Calcium Mol. Pharmacol. (IF 3.664) Pub Date : 2020-12-01 Douglas R. Miller; Habibeh Khoshbouei; Sumanta Garai; Lucas N. Cantwell; Clare Stokes; Ganesh Thakur; Roger L. Papke
The currents of α7 nicotinic acetylcholine receptors activated by acetylcholine (ACh) are brief. The channel has high permeability to calcium relative to monovalent cations and shows inward rectification. It has been previously noted that in the presence of positive allosteric modulators (PAMs), currents through the channels of α7 receptors differ from normal α7 currents both in sensitivity to specific
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MicroRNA-1291-5p Sensitizes Pancreatic Carcinoma Cells to Arginine Deprivation and Chemotherapy through the Regulation of Arginolysis and Glycolysis Mol. Pharmacol. (IF 3.664) Pub Date : 2020-12-01 Mei-Juan Tu; Zhijian Duan; Zhenzhen Liu; Chao Zhang; Richard J. Bold; Frank J. Gonzalez; Edward J. Kim; Ai-Ming Yu
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N-Terminal Targeting of Regulator of G Protein Signaling Protein 2 for F-Box Only Protein 44–Mediated Proteasomal Degradation Mol. Pharmacol. (IF 3.664) Pub Date : 2020-12-01 Harrison J. McNabb; Stephanie Gonzalez; Christine S. Muli; Benita Sjögren
Regulator of G protein signaling (RGS) proteins are negative modulators of G protein signaling that have emerged as promising drug targets to improve specificity and reduce side effects of G protein–coupled receptor–related therapies. Several small molecule RGS protein inhibitors have been identified; however, enhancing RGS protein function is often more clinically desirable but presents a challenge
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GZD824 Inhibits GCN2 and Sensitizes Cancer Cells to Amino Acid Starvation Stress Mol. Pharmacol. (IF 3.664) Pub Date : 2020-12-01 Yu Kato; Kazuhiro Kunimasa; Mizuki Takahashi; Ayaka Harada; Ikuko Nagasawa; Masanori Osawa; Yoshikazu Sugimoto; Akihiro Tomida
Eukaryotic initiation factor 2α (eIF2α) kinase general control nonderepressible 2 (GCN2) drives cellular adaptation to amino acid limitation by activating the integrated stress response that induces activating transcription factor 4 (ATF4). Here, we found that a multikinase inhibitor, GZD824, which we identified using a cell-based assay with ATF4 immunostaining, inhibited the GCN2 pathway in cancer
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The Influence of Tobacco Smoke/Nicotine on CYP2A Expression in Human and African Green Monkey Lungs Mol. Pharmacol. (IF 3.664) Pub Date : 2020-12-01 Yuan Gao; Sharon Miksys; Roberta M. Palmour; Rachel F. Tyndale
CYP2A enzymes metabolically inactivate nicotine and activate tobacco-derived procarcinogens [e.g., 4-[methylnitrosamino]-1-(3-pyridyl)-1-butanone]. Smoking decreases nicotine clearance, and chronic nicotine reduces hepatic CYP2A activity. However, little is known about the impact of smoking or nicotine on the expression of CYP2A in the lung. We investigated 1) the levels of human lung CYP2A mRNA in
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Structure of the Complex of an Iminopyridinedione Protein Tyrosine Phosphatase 4A3 Phosphatase Inhibitor with Human Serum Albumin Mol. Pharmacol. (IF 3.664) Pub Date : 2020-12-01 Mateusz P. Czub; Adam M. Boulton; Ettore J. Rastelli; Nikhil R. Tasker; Taber S. Maskrey; Isabella K. Blanco; Kelley E. McQueeney; John H. Bushweller; Wladek Minor; Peter Wipf; Elizabeth R. Sharlow; John S. Lazo
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Antiepileptic drug-activated constitutive androstane receptor inhibits peroxisome proliferator-activated receptor α- and peroxisome proliferator-activated receptor γ coactivator 1α-dependent gene expression to increase blood triglyceride levels. Mol. Pharmacol. (IF 3.664) Pub Date : 2020-11-01 Ryota Shizu,Yuta Otsuka,Kanako Ezaki,Chizuru Ishii,Shingo Arakawa,Yuto Amaike,Taiki Abe,Takuomi Hosaka,Takamitsu Sasaki,Yuichiro Kanno,Masaaki Miyata,Yasushi Yamazoe,Kouichi Yoshinari
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Molecular pharmacology of NRH:quinone oxidoreductase 2: A detoxifying enzyme acting as an undercover toxifying enzyme. Mol. Pharmacol. (IF 3.664) Pub Date : 2020-11-01 Elzbieta Janda,Françoise Nepveu,Barbara Calamini,Gilles Ferry,Jean A Boutin
N-ribosyldihydronicotinamide:quinone oxidoreductase 2 (NQO2/QR2, Enzyme Commission number 1.10.99.2) is a cytosolic enzyme, abundant in the liver and variably expressed in mammalian tissues. Cloned 30 years ago, it was characterized as a flavoenzyme catalyzing the reduction of quinones and pseudoquinones. To do so, it uses exclusively N-alkyl nicotinamide derivatives, without being able to recognize
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Heparin-binding peptides as novel therapies to stop SARS-CoV-2 cellular entry and infection. Mol. Pharmacol. (IF 3.664) Pub Date : 2020-11-01 Omid Tavassoly,Farinaz Safavi,Iman Tavassoly
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Arrestin recruitment to CCR5: potent CCL5 analogs reveal differences in dependence on receptor phosphorylation and isoform-specific recruitment bias. Mol. Pharmacol. (IF 3.664) Pub Date : 2020-11-01 Elsa Martins,Hellena Brodier,Irène Rossitto-Borlat,Ilke Ilgaz,Mélanie Villard,Oliver Hartley
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Transient Receptor Potential Ankyrin-1 (TRPA1) and Vanilloid-3 (TRPV3) Differentially Regulate Endoplasmic Reticulum Stress and Cytotoxicity in Human Lung Epithelial Cells Following Pneumotoxic Wood Smoke Particle Exposure. Mol. Pharmacol. (IF 3.664) Pub Date : 2020-11-01 Nam D Nguyen,Tosifa A Memon,Katherine L Burrell,Marysol Almestica-Roberts,Emmanuel Rapp,Lili Sun,Abigail F Scott,Cassandra Deering-Rice,Joseph E Rower,Christopher A Reilly
This study investigated the roles of transient receptor potential (TRP) ankyrin-1 (TRPA1) and TRP vanilloid-3 (TRPV3) in regulating endoplasmic reticulum stress (ERS) and cytotoxicity in human bronchial epithelial cells (HBECs) treated with pneumotoxic wood smoke particulate matter (WSPM) and chemical agonists of each channel. Functions of TRPA1 and TRPV3 in pulmonary epithelial cells remain largely
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Functions of the CXCL12-receptor ACKR3 / CXCR7 - What has been perceived and what has been overlooked. Mol. Pharmacol. (IF 3.664) Pub Date : 2020-11-01 Christian Koch,Jürgen Engele
The CXCL12 system is central to the development of many organs and is further crucially engaged in pathophysiological processes underlying cancer, inflammation, and cardiovascular disorders. This disease-associated role presently focuses major interest on the two CXCL12 receptors, CXCR4 and atypical chemokine receptor 3 (ACKR3)/CXCR7, as promising therapeutic targets. Major obstacles in these ongoing
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Notch 1 in cancer therapy: possible clinical implications and challenges. Mol. Pharmacol. (IF 3.664) Pub Date : 2020-11-01 Lobna Faiz Gharaibeh,Nirmeen Elmadany,Kholoud Alwosaibai,Walhan Alshaer
The Notch family consists of four highly conserved transmembrane receptors. The release of the active intracellular domain requires the enzymatic activity of γ-secretase. Notch is involved in embryonic development and in many physiologic processes of normal cells, in which it regulates growth, apoptosis, and differentiation. Notch1, a member of the Notch family, is implicated in many types of cancer
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Regulation of kappa opioid receptor inactivation depends on sex and cellular site of antagonist action. Mol. Pharmacol. (IF 3.664) Pub Date : 2020-11-01 Kathryn L Reichard,Keionna A Newton,Zeena M G Rivera,Paulo M Sotero de Menezes,Selena S Schattauer,Benjamin B Land,Charles Chavkin
The prototypical member of the receptor-inactivating kappa opioid receptor (KOR) antagonists, norbinaltorphimine (norBNI), produces prolonged receptor inactivation by a cJun kinase mechanism. These antagonists have potential therapeutic utility in the treatment of stress disorders; however, additional preclinical characterization is necessary to understand important aspects of their action. In this
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GS-967 and Eleclazine Block Sodium Channels in Human Induced Pluripotent Stem Cell-derived Cardiomyocytes. Mol. Pharmacol. (IF 3.664) Pub Date : 2020-11-01 Franck Potet,Defne E Egecioglu,Paul W Burridge,Alfred L George
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Structure of cytochrome P450 2C9*2 in complex with an anti-hypertensive drug losartan: Insights into the effect of genetic polymorphism. Mol. Pharmacol. (IF 3.664) Pub Date : 2020-11-01 Sonia J Parikh,Chiara M Evans,Juliet O Obi,Qinghai Zhang,Keiko Maekawa,Karen C Glass,Manish B Shah
The human CYP2C9 plays a crucial role in the metabolic clearance of a wide range of clinical therapeutics. The *2 allele is a prevalent genetic variation in CYP2C9 that is found in various populations. A marked reduction of catalytic activity toward many important drug substrates has been demonstrated by CYP2C9*2, which represents an amino acid variation at position 144 from arginine to cysteine. The
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A Truncated Six Transmembrane Splice Variant MOR-1G Enhances Expression of the Full-Length Seven Transmembrane μ-Opioid Receptor through Heterodimerization. Mol. Pharmacol. (IF 3.664) Pub Date : 2020-10-01 Tiffany Zhang,Jin Xu,Ying-Xian Pan
The μ-opioid receptor gene undergoes extensive alternative splicing to generate an array of splice variants. One group of splice variants excludes the first transmembrane (TM) domain and contains six TM domains. These 6TM variants are essential for the action of a novel class of analgesic drugs, including 3-iodobenzoyl-6β-naltrexamide, which is potent against a spectrum of pain models without exhibiting
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Fentanyl-Induced Block of hERG Channels Is Exacerbated by Hypoxia, Hypokalemia, Alkalosis, and the Presence of hERG1b. Mol. Pharmacol. (IF 3.664) Pub Date : 2020-10-01 Jared N Tschirhart,Shetuan Zhang
Human ether-a-go-go–related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium current (IKr) important for repolarization of cardiac action potentials. Drug-induced disruption of hERG channel function is a main cause of acquired long QT syndrome, which can lead to ventricular arrhythmias and sudden death. Illicit fentanyl use is associated with sudden
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Chronic Treatment with Morphine Disrupts Acute Kinase-Dependent Desensitization of GPCRs. Mol. Pharmacol. (IF 3.664) Pub Date : 2020-10-01 Emily R Leff,Seksiri Arttamangkul,John T Williams
Based on studies using mutations of the µ-opioid receptor (MOR), phosphorylation of multiple sites on the C-terminus has been recognized as a critical step underlying acute desensitization and the development of cellular tolerance. The aim of this study is to explore which kinases mediate desensitization of MOR in brain slices from drug-naïve and morphine-treated animals. Whole-cell recordings from
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Spinal Opioid Tolerance Depends upon Platelet-Derived Growth Factor Receptor-β Signaling, Not μ-Opioid Receptor Internalization. Mol. Pharmacol. (IF 3.664) Pub Date : 2020-10-01 S Puig,K E Barker,S R Szott,P T Kann,J S Morris,H B Gutstein
Opioids are some of the most potent analgesics available. However, their effectiveness is limited by the development of analgesic tolerance. Traditionally, tolerance was thought to occur by termination of μ-opioid receptor (MOR) signaling via desensitization and internalization. Contradictory findings led to a more recent proposal that sustained MOR signaling caused analgesic tolerance. However, this
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Atomic-Level Characterization of the Methadone-Stabilized Active Conformation of µ-Opioid Receptor. Mol. Pharmacol. (IF 3.664) Pub Date : 2020-10-01 Abhijeet Kapoor,Davide Provasi,Marta Filizola
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Unique Pharmacological Properties of the Kappa Opioid Receptor Signaling Through Gαz as Shown with Bioluminescence Resonance Energy Tranfer. Mol. Pharmacol. (IF 3.664) Pub Date : 2020-10-01 Miriam E Barnett,Brian I Knapp,Jean M Bidlack
Opioid receptors (ORs) convert extracellular messages to signaling events by coupling to the heterotrimeric G proteins, Gα•βγ. Classic pharmacological methods, such as [35S]GTPγS binding and inhibition of cyclic AMP production, allow for general opioid characterization, but they are subject to the varying endogenous Gα proteins in a given cell type. Bioluminescence resonance energy transfer (BRET)
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Neprilysin Controls the Synaptic Activity of Neuropeptides in the Intercalated Cells of the Amygdala. Mol. Pharmacol. (IF 3.664) Pub Date : 2020-10-01 G C Gregoriou,S D Patel,B L Winters,E E Bagley
Endogenous opioid peptides in the amygdala regulate many of our behaviors and emotional responses. In particular, the endogenous opioid enkephalin plays a significant role in regulating amygdala activity, but its action is strongly limited by peptidases, which degrade enkephalin into inactive fragments. Inhibiting peptidases may be an attractive method to enhance endogenous opioid signaling; however
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Bidirectional Relationship between Opioids and Disrupted Sleep: Putative Mechanisms. Mol. Pharmacol. (IF 3.664) Pub Date : 2020-10-01 D Eacret,S C Veasey,J A Blendy
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