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https://www.readbyqxmd.com/read/28935562/n-2-methoxyphenyl-benzenesulfonamide-a-novel-regulator-of-neuronal-g-protein-gated-inward-rectifier-k-channels
#1
Kenneth B Walsh, Elaine A Gay, Bruce E Blough, David W Geurkink
G protein-gated inward rectifier K(+) (GIRK) channels are members of the super-family of proteins known as inward rectifier K(+) (Kir) channels and are expressed throughout the peripheral and central nervous systems. Neuronal GIRK channels are the downstream targets of a number of neuromodulators including opioids, somatostatin, dopamine and cannabinoids. Previous studies have demonstrated that the ATP-sensitive K(+) channel, another member of the Kir channel family, is regulated by sulfonamide drugs. Therefore, to determine if sulfonamides also modulate GIRK channels, we screened a library of arylsulfonamide compounds using a GIRK channel fluorescent assay that utilized pituitary AtT20 cells expressing GIRK channels along with the somatostatin type-2 and -5 receptors...
September 18, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28935216/allosteric-modulators-targeting-cns-muscarinic-receptors
#2
REVIEW
Andreas Bock, Ramona Schrage, Klaus Mohr
Muscarinic acetylcholine receptors are G protein-coupled receptors (GPCRs) which are broadly expressed in the central nervous system (CNS) and other tissues in the periphery. They emerge as important drug targets for a number of diseases including Alzheimer's disease, Parkinson's disease, and schizophrenia. Muscarinic receptors are divided into five subtypes (M1-M5) of which M1-M4 have been crystalized. All subtypes possess at least one allosteric binding site which is located in the extracellular region of the receptor on top of the ACh (i...
September 18, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28934823/comprehensive-analysis-of-non-synonymous-natural-variants-of-g-protein-coupled-receptors
#3
Hee Ryung Kim, Nguyen Minh Duc, Ka Young Chung
G protein-coupled receptors (GPCRs) are the largest superfamily of transmembrane receptors and have vital signaling functions in various organs. Because of their critical roles in physiology and pathology, GPCRs are the most commonly used therapeutic target. It has been suggested that GPCRs undergo massive genetic variations such as genetic polymorphisms and DNA insertions or deletions. Among these genetic variations, non-synonymous natural variations change the amino acid sequence and could thus alter GPCR functions such as expression, localization, signaling, and ligand binding, which may be involved in disease development and altered responses to GPCR-targeting drugs...
September 19, 2017: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/28934222/endogenous-rgs14-is-a-cytoplasmic-nuclear-shuttling-protein-that-localizes-to-juxtanuclear-membranes-and-chromatin-rich-regions-of-the-nucleus
#4
Mary Rose Branch, John R Hepler
Regulator of G protein signaling 14 (RGS14) is a multifunctional scaffolding protein that integrates G protein and H-Ras/MAPkinase signaling pathways to regulate synaptic plasticity important for hippocampal learning and memory. However, to date, little is known about the subcellular distribution and roles of endogenous RGS14 in a neuronal cell line. Most of what is known about RGS14 cellular behavior is based on studies of tagged, recombinant RGS14 ectopically overexpressed in unnatural host cells. Here, we report for the first time a comprehensive assessment of the subcellular distribution and dynamic localization of endogenous RGS14 in rat B35 neuroblastoma cells...
2017: PloS One
https://www.readbyqxmd.com/read/28926402/reversing-hiv-latency-via-sphingosine-1-phosphate-receptor-1-signaling
#5
Charline Duquenne, Sandrine Gimenez, Adeline Guigues, Benjamin Viala, Caroline Boulouis, Clément Mettling, Damien Maurel, Noëlie Campos, Etienne Doumazane, Laetitia Comps-Agrar, Jamal Tazi, Laurent Prézeau, Pierre Corbeau, Vincent François
OBJECTIVE: In this study, we looked for a new family of latency reversing agents. DESIGN: We searched for G protein-coupled receptors (GPCR) coexpressed with CCR5 in primary CD4+ T cells that activate infected cells and boost HIV production. METHODS: GPCR coexpression was unveiled by RT-PCR. We used FRET to analyze the dimerization with CCR5 of the expressed GPCR. Viral entry was measured by flow cytometry, reverse transcription by quantitative PCR, NFkB translocation by immunofluorescence, LTR activation using a gene reporter assay, and viral production by p24 quantification...
September 18, 2017: AIDS
https://www.readbyqxmd.com/read/28912303/gpr62-constitutively-activates-camp-signaling-but-is-dispensable-for-male-fertility-in-mice
#6
Tomoyuki Muroi, Yuri Matsushima, Ryota Kanamori, Hikari Inoue, Wataru Fujii, Keiichiro Yogo
G-protein-coupled receptors (GPCRs) participate in diverse physiological functions and are promising targets for drug discovery. However, there are still over 140 orphan GPCRs whose functions remain to be elucidated. Gpr62 is one of the orphan GPCRs that is expressed in the rat and human brain. In this study, we found that Gpr62 is also expressed in male germ cells in mice, and its expression increases along with sperm differentiation. GPR62 lacks the BBXXB and DRY motifs, which are conserved across many GPCRs, and it was able to induce cAMP signaling in the absence of a ligand...
September 14, 2017: Reproduction: the Official Journal of the Society for the Study of Fertility
https://www.readbyqxmd.com/read/28912086/g-protein-coupled-receptor-kinase-4-induced-cellular-senescence-and-its-senescence-associated-gene-expression-profiling
#7
Pingping Xiao, Xishi Huang, Lanzhen Huang, Jing Yang, Ang Li, Ke Shen, Philip B Wedegaertner, Xiaoshan Jiang
Senescent cells have lost their capacity for proliferation and manifest as irreversibly in cell cycle arrest. Many membrane receptors, including G protein-coupled receptors (GPCRs), initiate a variety of intracellular signaling cascades modulating cell division and potentially play roles in triggering cellular senescence response. GPCR kinases (GRKs) belong to a family of serine/threonine kinases. Although their role in homologous desensitization of activated GPCRs is well established, the involvement of the kinases in cell proliferation is still largely unknown...
September 11, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28901275/reverse-induced-fit-driven-mas-downstream-transduction-looking-for-metabotropic-agonists
#8
Larissa Pernomian, Mayara Santos Gomes, Carlos Henrique Tomich de Paula da Silva, Joaquin Campos
The protective effects assigned to MAS receptors activation have spurred a great interest in the development of MAS agonists for clinical purposes. However, the current bases that drive the design of these ligands preclude important concepts recently addressed for MAS activation. Emerging data confirmed that physiological concentrations of peptide MAS agonists induce an atypical signaling that does not reach the metabotropic efficacy of constitutive MAS activation. The canonical activation of MAS-coupled G proteins is only achieved by supraphysiological concentrations of peptide MAS agonists or physiological concentrations of chemically modified analogues...
September 11, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28899696/serotonin-2a-receptor-disulfide-bridge-integrity-is-crucial-for-ligand-binding-to-different-signalling-states-but-not-for-its-homodimerization
#9
Alba Iglesias, Marta Cimadevila, Rocío Ailim de la Fuente, María Martí-Solano, María Isabel Cadavid, Marián Castro, Jana Selent, María Isabel Loza, José Brea
The serotonin 2A (5-HT2A) receptor is a G-protein coupled receptor (GPCR) with a conserved disulfide bridge formed by Cys(148) (transmembrane helix 3, TM3) and Cys(227) (extracellular loop 2, ECL-2). We hypothesized that disulfide bridges may determine serotonin 5-HT2A receptor functions such as receptor activation, functional selectivity and ligand recognition. We used the reducing agent dithiothreitol (DTT) to determine how the reduction of disulfide bridges affects radioligand binding, second messenger mobilization and receptor dimerization...
September 9, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28891236/a-disease-associated-mutation-in-the-adhesion-gpcr-bai2-adgrb2-increases-receptor-signaling-activity
#10
Ryan H Purcell, Camilo Toro, William A Gahl, Randy A Hall
Mutations in G protein-coupled receptors (GPCRs) that increase constitutive signaling activity can cause human disease. A de novo C-terminal mutation (R1465W) in the adhesion GPCR BAI2 (also known as ADGRB2) was identified in a patient suffering from progressive spastic paraparesis and other neurological symptoms. In vitro studies revealed that this mutation strongly increases the constitutive signaling activity of an N-terminally cleaved form of BAI2, which represents the activated form of the receptor. Further studies dissecting the mechanism(s) underling this effect revealed that wild-type BAI2 primarily couples to Gαz , with the R1465W mutation conferring increased coupling to Gαi ...
September 10, 2017: Human Mutation
https://www.readbyqxmd.com/read/28881079/formyl-peptide-receptors-in-mice-and-men-similarities-and-differences-in-recognition-of-conventional-ligands-and-modulating-lipopeptides
#11
Malene Winther, Claes Dahlgren, Huamei Forsman
The pattern recognition formyl peptide receptors (FPRs) belong to the class of G protein-coupled receptors (GPCRs), the largest group of cell-surface receptors involved in a range of physiological processes and pathologies. The FPRs have regulatory function in the initiation as well as resolution of inflammatory reactions, making them highly interesting as targets for drug development. Recent research in the GPCR/FPR fields has uncovered novel receptor biology concepts, including biased signalling/functional selectivity, allosteric modulation, receptor reactivation and receptor cross-talk...
September 7, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28880957/mapping-the-stk4-hippo-signaling-network-in-prostate-cancer-cell
#12
Damien Ready, Kader Yagiz, Pooneh Amin, Yuksel Yildiz, Vincent Funari, Serdar Bozdag, Bekir Cinar
Dysregulation of MST1/STK4, a key kinase component of the Hippo-YAP pathway, is linked to the etiology of many cancers with poor prognosis. However, how STK4 restricts the emergence of aggressive cancer remains elusive. Here, we investigated the effects of STK4, primarily localized in the cytoplasm, lipid raft, and nucleus, on cell growth and gene expression in aggressive prostate cancer. We demonstrated that lipid raft and nuclear STK4 had superior suppressive effects on cell growth in vitro and in vivo compared with cytoplasmic STK4...
2017: PloS One
https://www.readbyqxmd.com/read/28875842/targeting-cxcl12-cxcr4-axis-in-tumor-immunotherapy
#13
Weiqiang Zhou, Shanchun Guo, Mingli Liu, Matthew E Burow, Guangdi Wang
Chemokines, which have chemotactic abilities, are comprised of over 50 family members. Through binding to the 7-transmembrane domain of G-protein-coupled receptors (GPCR), they function in immune cells by trafficking and regulating cell prolif¬eration, differentiation, activation, and migration, homing under both physiologic and pathologic conditions. The alpha-chemokine receptor CXCR4 for the alpha-chemokine stromal cell-derived-factor-1 (SDF-1) is most widely expressed by tumors. CXCL12/CXCR4 axis is a major culprit for human tumor because of its crucial role in tumor initiation and progression by activating a number of signaling pathways, such as ERK1/2, ras, PLC/ MAPK, p38 MAPK, and SAPK/ JNK, as well as regulating cancer stem cells...
August 29, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28874659/internalized-tsh-receptors-en-route-to-the-tgn-induce-local-gs-protein-signaling-and-gene-transcription
#14
Amod Godbole, Sandra Lyga, Martin J Lohse, Davide Calebiro
A new paradigm of G-protein-coupled receptor (GPCR) signaling at intracellular sites has recently emerged, but the underlying mechanisms and functional consequences are insufficiently understood. Here, we show that upon internalization in thyroid cells, endogenous TSH receptors traffic retrogradely to the trans-Golgi network (TGN) and activate endogenous Gs-proteins in the retromer-coated compartment that brings them to the TGN. Receptor internalization is associated with a late cAMP/protein kinase A (PKA) response at the Golgi/TGN...
September 5, 2017: Nature Communications
https://www.readbyqxmd.com/read/28874589/dual-role-of-mitochondria-in-producing-melatonin-and-driving-gpcr-signaling-to-block-cytochrome-c-release
#15
Yalikun Suofu, Wei Li, Frédéric G Jean-Alphonse, Jiaoying Jia, Nicolas K Khattar, Jiatong Li, Sergei V Baranov, Daniela Leronni, Amanda C Mihalik, Yanqing He, Erika Cecon, Vanessa L Wehbi, JinHo Kim, Brianna E Heath, Oxana V Baranova, Xiaomin Wang, Matthew J Gable, Eric S Kretz, Giulietta Di Benedetto, Timothy R Lezon, Lisa M Ferrando, Timothy M Larkin, Mara Sullivan, Svitlana Yablonska, Jingjing Wang, M Beth Minnigh, Gérald Guillaumet, Franck Suzenet, R Mark Richardson, Samuel M Poloyac, Donna B Stolz, Ralf Jockers, Paula A Witt-Enderby, Diane L Carlisle, Jean-Pierre Vilardaga, Robert M Friedlander
G protein-coupled receptors (GPCRs) are classically characterized as cell-surface receptors transmitting extracellular signals into cells. Here we show that central components of a GPCR signaling system comprised of the melatonin type 1 receptor (MT1), its associated G protein, and β-arrestins are on and within neuronal mitochondria. We discovered that the ligand melatonin is exclusively synthesized in the mitochondrial matrix and released by the organelle activating the mitochondrial MT1 signal-transduction pathway inhibiting stress-mediated cytochrome c release and caspase activation...
September 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28874462/%C3%AE-arrestin2-improves-post-myocardial-infarction-heart-failure-via-sarco-endo-plasmic-reticulum-ca-2-atpase-dependent-positive-inotropy-in-cardiomyocytes
#16
Katie A McCrink, Jennifer Maning, Angela Vu, Malika Jafferjee, Christine Marrero, Ava Brill, Ashley Bathgate-Siryk, Samalia Dabul, Walter J Koch, Anastasios Lymperopoulos
Heart failure is the leading cause of death in the Western world, and new and innovative treatments are needed. The GPCR (G protein-coupled receptor) adapter proteins βarr (β-arrestin)-1 and βarr-2 are functionally distinct in the heart. βarr1 is cardiotoxic, decreasing contractility by opposing β1AR (adrenergic receptor) signaling and promoting apoptosis/inflammation post-myocardial infarction (MI). Conversely, βarr2 inhibits apoptosis/inflammation post-MI but its effects on cardiac function are not well understood...
September 5, 2017: Hypertension
https://www.readbyqxmd.com/read/28874459/protease-activated-receptor-2-activates-airway-apical-membrane-chloride-permeability-and-increases-ciliary-beating
#17
Derek B McMahon, Alan D Workman, Michael A Kohanski, Ryan M Carey, Jenna R Freund, Benjamin M Hariri, Bei Chen, Laurel J Doghramji, Nithin D Adappa, James N Palmer, David W Kennedy, Robert J Lee
Mucociliary clearance, driven by the engine of ciliary beating, is the primary physical airway defense against inhaled pathogens and irritants. A better understanding of the regulation of ciliary beating and mucociliary transport is necessary for identifying new receptor targets to stimulate improved clearance in airway diseases, such as cystic fibrosis and chronic rhinosinusitis. In this study, we examined the protease-activated receptor (PAR)-2, a GPCR previously shown to regulate airway cell cytokine and mucus secretion, and transepithelial Cl(-) current...
September 5, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28872669/gpcr-signaling-from-within-the-cell
#18
REVIEW
Yuh-Jiin I Jong, Steven K Harmon, Karen L O'Malley
Traditionally, signal transduction from G protein-coupled receptors (GPCRs) is thought to emanate from the cell surface where receptor interactions with external stimuli can be transformed into a broad range of cellular responses. However, emergent data show that numerous GPCRs are also associated with various intracellular membranes where they may couple to different signaling systems, display unique desensitization patterns, and/or exhibit distinct patterns of subcellular distribution. Although many GPCRs can be activated at the cell surface and subsequently endocytosed and transported to a unique intracellular site, other intracellular GPCRs can be activated in situ either via de novo ligand synthesis, diffusion of permeable ligands or active transport of nonpermeable ligands...
September 5, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28864771/two-independent-but-synchronized-g%C3%AE-%C3%AE-subunit-controlled-pathways-are-essential-for-trailing-edge-retraction-during-macrophage-migration
#19
Praneeth Siripurapu, Dinesh Kankanamge, Kasun Ratnayake, Kanishka Senarath, Ajith Karunarathne
Chemokine-induced directional cell migration is a universal cellular mechanism and plays crucial roles in numerous biological processes, including embryonic development, immune system function, and tissue remodeling and regeneration. During the migration of a stationary cell, the cell polarizes, forms lamellipodia at the leading edge (LE), and triggers the concurrent retraction of the trailing edge (TE). During cell migration governed by inhibitory G protein (Gi)-coupled receptors (GPCRs), G protein Gβγ (Gβγ) subunits control the LE signaling...
September 1, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28864555/distinct-signaling-patterns-of-allosteric-antagonism-at-the-p2y1-receptor
#20
Zhan-Guo Gao, Kenneth A Jacobson
Traditionally, GPCR antagonists are classified as competitive or non-competitive and surmountable or insurmountable based on functional antagonism. P2Y1 receptor (P2Y1R) structures showed two antagonists binding to two spatially distinct sites: nucleotide MRS2500 (orthosteric, contacting the helical bundle) and urea BPTU (allosteric, on the external receptor surface). However, the nature of their P2Y1R antagonism has not been characterized. Here we characterized BPTU antagonism at various signaling pathways activated by structurally diverse agonists...
September 1, 2017: Molecular Pharmacology
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