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M Young, T Dahoun, B Sokrat, C Arber, K M Chen, M Bouvier, P Barth
Membrane receptors regulate numerous intracellular functions. However, the molecular underpinnings remain poorly understood because most receptors initiate multiple signaling pathways through distinct interaction interfaces that are structurally uncharacterized. We present an integrated computational and experimental approach to model and rationally engineer membrane receptor-intracellular protein systems signaling with novel pathway selectivity. We targeted the dopamine D2 receptor (D2), a G-protein-coupled receptor (GPCR), which primarily signals through Gi, but triggers also the Gq and beta-arrestin pathways...
June 18, 2018: Proceedings of the National Academy of Sciences of the United States of America
M Saarnilehto, M Pekkanen-Mattila, K Aalto-Setälä, O Silvennoinen, A Koivisto
Aims Aim of the study was to characterize functional ion channel and GPCR responses by using selective pharmacological tools and intracellular calcium imaging from human inducible pluripotent stem cell-derived sensory neurons. Methods Sensory neurons were generated from human keratinocytes that were reprogrammed to inducible pluripotent stem cells by using standard Yamanaka factors. Inducible pluripotent stem cells were differentiated into sensory neurons by using 2 differentiation protocols (small molecule and PA6 co-culture)...
December 29, 2017: Scandinavian Journal of Pain
Bruck Taddese, Madeline Deniaud, Antoine Garnier, Asma Tiss, Hajer Guissouma, Hervé Abdi, Daniel Henrion, Marie Chabbert
Chemokines and their receptors (members of the GPCR super-family) are involved in a wide variety of physiological processes and diseases; thus, understanding the specificity of the chemokine receptor family could help develop new receptor specific drugs. Here, we explore the evolutionary mechanisms that led to the emergence of the chemokine receptors. Based on GPCR hierarchical classification, we analyzed nested GPCR sets with an eigen decomposition approach of the sequence covariation matrix and determined three key residues whose mutation was crucial for the emergence of the chemokine receptors and their subsequent divergence into homeostatic and inflammatory receptors...
June 18, 2018: PLoS Computational Biology
Jian Chen, Qian Wang, Wei Zhou, Zheng Zhou, Peng-Yu Tang, Tao Xu, Wei Liu, Lin-Wei Li, Lin Cheng, Zhi-Min Zhou, Jin Fan, Guo-Yong Yin
GPCR kinase 2-interacting protein-1 (GIT1) is a scaffold protein that plays an important role in cell adaptation, proliferation, migration, and differentiation; however, the role of GIT1 in the regulation of neuronal death after spinal cord injury remains obscure. Here, we demonstrate that GIT1 deficiency remarkably increased neuronal apoptosis and enhanced JNK/p38 signaling, which resulted in stronger motor deficits by ischemia-reperfusion in vivo, consistent with the finding of oxygen-glucose deprivation/reoxygenation-induced neuronal injury in vitro...
June 18, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
A Lesniak, A Jonsson, M Aarnio, T Norberg, F Nyberg, T Gordh
Aims In PET studies of patients suffering from chronic pain following whip lash trauma, d-deprenyl was shown to bind to painful sites in the neck [1]. High uptake points towards an existence of an inflammation-specific binding site. Thus, the aim of this study was to identify the binding site for d-deprenyl employing radioligand receptor binding and high-throughput analysis of its activity towards 165 G-protein coupled receptors and 84 enzyme targets commonly used in drug discovery and development. Methods D-Deprenyl activity towards GPCR targets was assessed by DiscoverX in CHO-K1 EDG1 β-arrest in EFC cell line utilizing the PathHunter™ technique...
December 29, 2017: Scandinavian Journal of Pain
Wei Wang, Zhao-Xia Chen, Dong-Yu Guo, Ya-Xiong Tao
Regulation of prostate cancer by androgen and androgen receptor (AR), and blockade of AR signaling by AR antagonists and steroidogenic enzyme inhibitors have been extensively studied. G protein-coupled receptors (GPCRs) are a family of membrane receptors that regulate almost all physiological processes. Nearly 40% of FDA-approved drugs in the market target GPCRs. A variety of GPCRs that mediate reproductive function have been demonstrated to be involved in the regulation of prostate cancer. These GPCRs include gonadotropin-releasing hormone receptor, luteinizing hormone receptor, follicle-stimulating hormone receptor, relaxin receptor, ghrelin receptor, and kisspeptin receptor...
June 15, 2018: Pharmacology & Therapeutics
Dharendra Thapa, Michael W Stoner, Manling Zhang, Bingxian Xie, Janet R Manning, Danielle Guimaraes, Sruti Shiva, Michael J Jurczak, Iain Scott
Mitochondria supply ~90% of the ATP required for contractile function in cardiac cells. While adult cardiomyocytes preferentially utilize fatty acids as a fuel source for oxidative phosphorylation, cardiac mitochondria can switch to other substrates when required. This change is driven in part by a combination of extracellular and intracellular signal transduction pathways that alter mitochondrial gene expression and enzymatic activity. The mechanisms by which extracellular metabolic information is conveyed to cardiac mitochondria are not currently well defined...
June 9, 2018: Redox Biology
Iva Hopkins Navratilova, Tonia Aristotelous, Louise E Bird, Andrew L Hopkins
Biophysical screening techniques, such as surface plasmon resonance, enable detailed kinetic analysis of ligands binding to solubilised G-protein coupled receptors. The activity of a receptor solubilised out of the membrane is crucially dependent on the environment in which it is suspended. Finding the right conditions is challenging due to the number of variables to investigate in order to determine the optimum solubilisation buffer for any given receptor. In this study we used surface plasmon resonance technology to screen a variety of solubilisation conditions including buffers and detergents for two model receptors: CXCR4 and CCR5...
June 14, 2018: Analytical Biochemistry
András D Tóth, Richard Schell, Magdolna Lévay, Christiane Vettel, Philipp Theis, Clemens Haslinger, Felix Alban, Stefanie Werhahn, Lina Frischbier, Jutta Krebs-Haupenthal, Dominique Thomas, Hermann-Josef Gröne, Metin Avkiran, Hugo A Katus, Thomas Wieland, Johannes Backs
The myocyte enhancer factor 2 (MEF2) regulates transcription in cardiac myocytes and adverse remodeling of adult hearts. Activators of G protein-coupled receptors (GPCRs) have been reported to activate MEF2, but a comprehensive analysis of GPCR activators that regulate MEF2 has to our knowledge not been performed. Here, we tested several GPCR agonists regarding their ability to activate a MEF2 reporter in neonatal rat ventricular myocytes. The inflammatory mediator prostaglandin E2 (PGE2 ) strongly activated MEF2...
June 15, 2018: EMBO Molecular Medicine
Danping Liu, Jian Li, Wei Lu, Yanbing Wang, Xinlan Zhou, Dan Huang, Xiufen Li, Rongrong Ding, Zhanqing Zhang
OBJECTIVE: To evaluate the performance of a new mathematical model gamma- glutamyl transpeptidase to cholinesterase and platelet ratio (GCPR) versus gamma- glutamyl transpeptidase to platelet ratio (GPR) in predicting significant fibrosis and cirrhosis of chronic hepatitis B (CHB). METHODS: A complete cohort of 2343 patients was divided into early and late cohort depending on the time of liver biopsy. With reference to the Scheuer standard, liver pathological stage ≥S2 and ≥S4 were defined as significant fibrosis and cirrhosis, respectively...
June 12, 2018: Clinical Microbiology and Infection
Ruby M Lam, Alexander T Chesler
No abstract text is available yet for this article.
June 14, 2018: Journal of General Physiology
K E Quinn, D I Mackie, K M Caron
The discovery that atypical chemokine receptors (ACKRs) can initiate alternative signaling pathways rather than classical G-protein coupled receptor (GPCR) signaling has changed the paradigm of chemokine receptors and their roles in modulating chemotactic responses. The ACKR family has grown over the years, with discovery of new functions and roles in a variety of pathophysiological conditions. However, the extent to which these receptors regulate normal physiology is still continuously expanding. In particular, atypical chemokine receptor 3 (ACKR3) has proven to be an important receptor in mediating normal biological functions, including cardiac development and migration of cortical neurons...
September 2018: Cytokine
Clara T Schoeder, Maria Kaleta, Andhika B Mahardhika, Agnieszka Olejarz-Maciej, Dorota Łażewska, Katarzyna Kieć-Kononowicz, Christa E Müller
GPR18 is a cannabinoid-activated orphan G protein-coupled receptor (GPCR) that is selectively expressed on immune cells. Despite its significant potential as a drug target for inflammatory diseases and cancer immunotherapy, only very few GPR18 ligands have been described to date. In the present study we investigated the structure-activity relationships (SARs) of (Z)-2-(3-(4-chlorobenzyloxy)benzylidene)-6,7-dihydro-2H-imidazo[2,1-b][1,3]thiazin-3(5H)-one (PSB-CB5, 5), the most potent GPR18 antagonist described to date...
June 1, 2018: European Journal of Medicinal Chemistry
Chen Chen, Brittney N Nguyen, Gabriel Mitchell, Shally R Margolis, Darren Ma, Daniel A Portnoy
Listeriolysin O (LLO) is a cholesterol-dependent cytolysin that mediates escape of Listeria monocytogenes from a phagosome, enabling growth of the bacteria in the host cell cytosol. LLO contains a PEST-like sequence that prevents it from killing infected cells, but the mechanism involved is unknown. We found that the LLO PEST-like sequence was necessary to mediate removal of LLO from the interior face of the plasma membrane, where it coalesces into discrete puncta. LLO interacts with Ap2a2, an adaptor protein involved in endocytosis, via its PEST-like sequence, and Ap2a2-dependent endocytosis is required to prevent LLO-induced cytotoxicity...
June 13, 2018: Cell Host & Microbe
Yogesh Bhattarai, Brianna B Williams, Eric J Battaglioli, Weston R Whitaker, Lisa Till, Madhusudan Grover, David R Linden, Yasutada Akiba, Karunya K Kandimalla, Nicholas C Zachos, Jonathan D Kaunitz, Justin L Sonnenburg, Michael A Fischbach, Gianrico Farrugia, Purna C Kashyap
Tryptamine, a tryptophan-derived monoamine similar to 5-hydroxytryptamine (5-HT), is produced by gut bacteria and is abundant in human and rodent feces. However, the physiologic effect of tryptamine in the gastrointestinal (GI) tract remains unknown. Here, we show that the biological effects of tryptamine are mediated through the 5-HT4 receptor (5-HT4 R), a G-protein-coupled receptor (GPCR) uniquely expressed in the colonic epithelium. Tryptamine increases both ionic flux across the colonic epithelium and fluid secretion in colonoids from germ-free (GF) and humanized (ex-GF colonized with human stool) mice, consistent with increased intestinal secretion...
June 13, 2018: Cell Host & Microbe
John F Cryan, Gerard Clarke, Timothy G Dinan, Harriet Schellekens
While there is growing appreciation that the microbiome regulates gut-brain signaling, the underlying mechanisms remain elusive. In this issue of Cell Host & Microbe, Bhattarai et al. (2018) identify bacteria-derived tryptamine as a ligand for the gut-epithelium-expressed GPCR 5-HT4 receptor, thereby functioning as a regulator of gastrointestinal motility.
June 13, 2018: Cell Host & Microbe
Antoine Koehl, Hongli Hu, Shoji Maeda, Yan Zhang, Qianhui Qu, Joseph M Paggi, Naomi R Latorraca, Daniel Hilger, Roger Dawson, Hugues Matile, Gebhard F X Schertler, Sebastien Granier, William I Weis, Ron O Dror, Aashish Manglik, Georgios Skiniotis, Brian K Kobilka
The μ-opioid receptor (μOR) is a G-protein-coupled receptor (GPCR) and the target of most clinically and recreationally used opioids. The induced positive effects of analgesia and euphoria are mediated by μOR signalling through the adenylyl cyclase-inhibiting heterotrimeric G protein Gi . Here we present the 3.5 Å resolution cryo-electron microscopy structure of the μOR bound to the agonist peptide DAMGO and nucleotide-free Gi . DAMGO occupies the morphinan ligand pocket, with its N terminus interacting with conserved receptor residues and its C terminus engaging regions important for opioid-ligand selectivity...
June 13, 2018: Nature
Elizabeth J English, Sarah A Mahn, Adriano Marchese
Signaling activated by binding of the C-X-C motif chemokine ligand CXCL12 to its cognate G protein-coupled receptor (GPCR), chemokine C-X-C motif receptor 4 (CXCR4), is linked to metastatic disease. Yet the mechanisms governing CXCR4 signaling remain poorly understood. Here we show that endocytosis and early endosome antigen 1 (EEA1), which is part of the endosome fusion machinery, are required for CXCL12-mediated AKT Ser/Thr kinase (Akt) signaling selective for certain Akt substrates. Pharmacological inhibition of endocytosis partially attenuated CXCL12-induced phosphorylation of Akt, but not phosphorylation of ERK-1/2...
June 13, 2018: Journal of Biological Chemistry
Masami Ikeda, Minoru Sugihara, Makiko Suwa
We report the development of the SEVENS database, which contains information on G-protein coupled receptor (GPCR) genes that are identified with high confidence levels (A, B, C, and D) from various eukaryotic genomes, by using a pipeline comprising bioinformatics softwares, including a gene finder, a sequence alignment tool, a motif and domain assignment tool, and a transmembrane helix predictor. SEVENS compiles detailed information on GPCR genes, such as chromosomal mapping position, phylogenetic tree, sequence similarity to known genes, and protein function described by motif/domain and transmembrane helices...
2018: Biophysics and Physicobiology
Kang Li, Qiang-Qiang Jia, Sheng Li
Since it was first postulated by Wigglesworth in 1934, juvenile hormone (JH) is considered a status-quo hormone in insects because it prevents metamorphosis that is initiated by the molting hormone (20-hydroxyecdysone, 20E). During the last decade, significant advances have been made regarding JH signaling. First, the bHLH-PAS transcription factor Met/Gce was identified as the JH intracellular receptor. In the presence of JH, with the assistance of Hsp83, and through physical association with a bHLH-PAS transcriptional co-activator, Met/Gce enters the nucleus and binds to E-box-like motifs in promoter regions of JH primary-response genes for inducing gene expression...
June 11, 2018: Insect Science
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