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G protein coupled receptor

Pradipta Ray, Andrew Torck, Lilyana Quigley, Andi Wangzhou, Matthew Neiman, Chandranshu Rao, Tiffany Lam, Ji-Young Kim, Tae Hoon Kim, Michael Q Zhang, Gregory Dussor, Theodore J Price
Molecular neurobiological insight into human nervous tissues is needed to generate next generation therapeutics for neurological disorders like chronic pain. We obtained human Dorsal Root Ganglia (DRG) samples from organ donors and performed RNA-sequencing (RNA-seq) to study the human DRG (hDRG) transcriptional landscape, systematically comparing it with publicly available data from a variety of human and orthologous mouse tissues, including mouse DRG (mDRG). We characterized the hDRG transcriptional profile in terms of tissue-restricted gene co-expression patterns and putative transcriptional regulators, and formulated an information-theoretic framework to quantify DRG enrichment...
March 20, 2018: Pain
Thomas D'huys, Sandra Claes, Tom Van Loy, Dominique Schols
Chemokine receptors CCR5 and CXCR4 are considered the main coreceptors for initial HIV infection, replication and transmission, and subsequent AIDS progression. Over the years, other chemokine receptors, belonging to the family of G protein-coupled receptors, have also been identified as candidate coreceptors for HIV entry into human host cells. Amongst them, CXCR7, also known as atypical chemokine receptor 3 (ACKR3), was suggested as a coreceptor candidate capable of facilitating both HIV-1 and HIV-2 entry in vitro ...
March 2018: Heliyon
Wanchao Yin, X Edward Zhou, Dehua Yang, Parker W de Waal, Meitian Wang, Antao Dai, Xiaoqing Cai, Chia-Ying Huang, Ping Liu, Xiaoxi Wang, Yanting Yin, Bo Liu, Yu Zhou, Jiang Wang, Hong Liu, Martin Caffrey, Karsten Melcher, Yechun Xu, Ming-Wei Wang, H Eric Xu, Yi Jiang
5-hydroxytryptamine (5-HT, also known as serotonin) regulates many physiological processes through the 5-HT receptor family. Here we report the crystal structure of 5-HT1B subtype receptor (5-HT1B R) bound to the psychotropic serotonin receptor inverse agonist methiothepin (MT). Crystallization was facilitated by replacing ICL3 with a novel optimized variant of BRIL (OB1) that enhances the formation of intermolecular polar interactions, making OB1 a potential useful tool for structural studies of membrane proteins...
2018: Cell Discovery
Skanda Rajasundaram
Our increasing appreciation of adenosine as an endogenous signaling molecule that terminates inflammation has generated excitement regarding the potential to target adenosine receptors (ARs) in the treatment of multiple sclerosis (MS), a disease of chronic neuroinflammation. Of the four G protein-coupled ARs, A2ARs are the principal mediator of adenosine's anti-inflammatory effects and accordingly, there is a growing body of evidence surrounding the role of A2ARs in experimental autoimmune encephalomyelitis (EAE), the dominant animal model of MS...
2018: Frontiers in Immunology
Jude Masannat, Hamsa Thayele Purayil, Yushan Zhang, Michelle Russin, Iqbal Mahmud, Wanju Kim, Daiqing Liao, Yehia Daaka
Renal Cell Carcinoma (RCC) is one of the most lethal urological cancers worldwide. The disease does not present early clinical symptoms and is commonly diagnosed at an advanced stage. Limited molecular drivers have been identified for RCC, resulting in the lack of effective treatment for patients with progressive disease. Ubiquitous βArrestin2 (βArr2) is well established for its function in the desensitization and trafficking of G protein-coupled receptors. More recently, βArr2 has been implicated in the regulation of fundamental cellular functions, including proliferation and invasion...
March 20, 2018: Scientific Reports
Sean Conroy, Nicholas D Kindon, Jacqueline Glenn, Leigh A Stoddart, Richard James Lewis, Stephen J Hill, Barrie Kellam, Michael John Stocks
The human P2Y2 receptor (hP2Y2R) is a G protein-coupled receptor that shows promise as a therapeutic target for many important conditions including anti-metastatic cancer therapy and more recently for the treatment of idiopathic pulmonary fibrosis. As such, there is a need for new hP2Y2R antagonists and molecular probes to study this receptor. Herein, we report the development of a new series of non-nucleotide hP2Y2R antagonists leading to the discovery of a series of fluorescent ligands containing different linkers and fluorophores based on the known, non-nucleotide hP2Y2R antagonist AR-C118925 (1)...
March 20, 2018: Journal of Medicinal Chemistry
Akifumi Kogame, Ronald Lee, Liping Pan, Miyako Sudo, Masami Nonaka, Yuu Moriya, Tomoaki Higuchi, Yoshihiko Tagawa
1. The absorption, distribution, metabolism and excretion of fasiglifam were investigated in rats, dogs, and humans. 2. The absolute oral bioavailability of fasiglifam was high in all species (> 76.0%). 3. After oral administration of [14 C]fasiglifam, the administered radioactivity was quantitatively recovered and the major route of excretion of radioactivity was via feces in all species. 4. Fasiglifam was a major component in the plasma and feces in all species. Its oxidative metabolite (M-I) was observed as a minor metabolite in rat and human plasma (< 10% of plasma radioactivity)...
March 20, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Adi L Tarca, Xiaofeng Gong, Roberto Romero, Wenxin Yang, Zhongqu Duan, Hao Yang, Chengfang Zhang, Peixuan Wang
Crowdsourcing has emerged as a framework to address methodological challenges in omics data analysis and assess the extent to which omics data are predictive of phenotypes of interest. The sbv IMPROVER Systems Toxicology Challenge was designed to leverage crowdsourcing to determine whether human blood gene expression levels are informative of current and past smoking. Participating teams were invited to use a training gene expression dataset to derive parsimonious models (up to 40 genes) that can accurately classify subjects into exposure groups: smokers, former smokers that quit for at least one year, and never-smokers...
February 2018: Computational Toxicology
Louisa Stern, Nathalia Giese, Thilo Hackert, Oliver Strobel, Peter Schirmacher, Klaus Felix, Matthias M Gaida
Bitter taste receptors (T2Rs) are G-protein coupled transmembrane proteins initially identified in the gustatory system as sensors for the taste of bitter. Recent evidence on expression of these receptors outside gustatory tissues suggested alternative functions, and there is growing interest of their potential role in cancer biology. In this study, we report for the first time, expression and functionality of the bitter receptor family member T2R10 in both human pancreatic ductal adenocarcinoma (PDAC) tissue and PDAC derived cell lines...
2018: Journal of Cancer
Mitsuaki Nishioka, Yutaka Suehiro, Kouhei Sakai, Toshihiko Matsumoto, Naoko Okayama, Hidekazu Mizuno, Koji Ueno, Nobuaki Suzuki, Shinichi Hashimoto, Taro Takami, Shoichi Hazama, Hiroaki Nagano, Isao Sakaida, Takahiro Yamasaki
Tumor necrosis factor receptor superfamily member 19 ( TROY ) is involved in the Wnt/β-catenin signaling pathway and interacts with leucine-rich repeat containing G-protein-coupled receptor 5 (LGR5), which is a well-known biomarker of cancer stem cells and a prognostic marker of colorectal cancer (CRC). Because there have been no studies to evaluate the prognostic significance of TROY , we performed the present study to determine whether TROY can be a prognostic biomarker in CRC patients. We evaluated TROY expression levels in 100 CRC tissues by quantitative real-time PCR and investigated the association of TROY expression levels with clinicopathologic features...
April 2018: Oncology Letters
Yilin Jiang, Junjie Miao, Dongliang Wang, Jingru Zhou, Bo Liu, Feng Jiao, Jiangfeng Liang, Yangshuo Wang, Cungang Fan, Qingjun Zhang
Significant antitumor activity of Momordica anti-human immunodeficiency virus protein of 30 kDa (MAP30) purified from Momordica charantia has been the subject of previous research. However, the effective mechanism of MAP30 on malignant glioma cells has not yet been clarified. The aim of the present study was to investigate the effects and mechanism of MAP30 on U87 and U251 cell lines. A Cell Counting Kit-8 assay, wound healing assay and Transwell assay were used to detect the effects on U87 and U251 cells treated with different concentrations of MAP30 (0...
April 2018: Oncology Letters
Daniel Mattle, Bernd Kuhn, Johannes Aebi, Marc Bedoucha, Demet Kekilli, Nathalie Grozinger, Andre Alker, Markus G Rudolph, Georg Schmid, Gebhard F X Schertler, Michael Hennig, Jörg Standfuss, Roger J P Dawson
In the degenerative eye disease retinitis pigmentosa (RP), protein misfolding leads to fatal consequences for cell metabolism and rod and cone cell survival. To stop disease progression, a therapeutic approach focuses on stabilizing inherited protein mutants of the G protein-coupled receptor (GPCR) rhodopsin using pharmacological chaperones (PC) that improve receptor folding and trafficking. In this study, we discovered stabilizing nonretinal small molecules by virtual and thermofluor screening and determined the crystal structure of pharmacologically stabilized opsin at 2...
March 19, 2018: Proceedings of the National Academy of Sciences of the United States of America
Shiying Liu, Yue Yin, Ruili Yu, Yin Li, Weizhen Zhang
BACKGROUND & AIMS: Leucine-rich repeat G-protein-coupled receptor 4 (LGR4) and its ligands R-spondin1-4 (Rspos) have been vastly investigated in embryonic development. The biological functions of Rspos-LGR4 system in liver remains largely unknown. Here, we explored whether it protects hepatocytes against hypoxia/reoxygenation (H/R) induced damage. METHODS: H/R injury was induced by dimethyloxalylglycine (DMOG) in AML12 cells and the effects of Rspo3 on cell proliferation and apoptosis were assessed...
March 16, 2018: Biochemical and Biophysical Research Communications
Scott R Gilbertson, Ying-Chu Chen, Claudia A Soto, Yaxing Yang, Kenner C Rice, Kathryn A Cunningham, Noelle C Anastasio
The approach of tethering together two known receptor ligands, to be used as molecular probes for the study of G protein-coupled receptor (GPCR) systems, has proven to be a valuable approach. Selective ligands that possess functionality that can be used to link to other ligands, are useful in the development of novel antagonists and agonists. Such molecules can also be attached to reporter molecules, such as fluorophores, for the study of GPCR dimerization and its role in signaling. The highly selective serotonin (5-HT) 5-HT2A receptor (5-HT2A R) antagonist M100907 (volinanserin) is of clinical interest in the treatment of neurological and mental health disorders...
March 16, 2018: Bioorganic & Medicinal Chemistry Letters
Andrii Ishchenko, Cornelius Gati, Vadim Cherezov
G protein-coupled receptors mediate cell signaling and regulate the majority of sensory and physiological processes in the human body. Recent breakthroughs in cryo-electron microscopy and X-ray free electron lasers have accelerated structural studies of difficult-to-crystallize receptors and their signaling complexes, and have opened up new opportunities in understanding conformational dynamics and visualizing the process of receptor activation with unprecedented spatial and temporal resolution. Here, we summarize major milestones and challenges associated with the application of these techniques and outline future directions in their development with a focus on membrane protein structural biology...
March 16, 2018: Current Opinion in Structural Biology
Xiaozhen Yang, Genyong Huang, Min-Jie Xu, Cong Zhang, Yongxu Cheng, Zhigang Yang
Dopamine (DA) plays a modulatory role in numerous physiological processes such as light adaptation and food intake, and exerts these functions through DA receptors (DARs). This study presents, for the first time, isolation and characterization of the dopamine receptor 2(DA2 receptor) cDNA from the intestinal tissue of Eriocheir sinensis, an economically important freshwater aquaculture species in China. The DA2 receptor cDNA sequence, which was obtained by rapid amplification of cDNA ends, is 2369bp long, encode peptide of 589 amino acid, and is highly homologous to related sequences in crustaceans...
2018: PloS One
Sandra Claes, Thomas D'huys, Anneleen Van Hout, Dominique Schols, Tom Van Loy
G protein-coupled receptors (GPCRs) are of great importance to the pharmaceutical industry as they are involved in many human diseases and include well-validated targets for therapeutic intervention. Discovery of lead compounds, including small synthetic molecules, that specifically inhibit the receptor's function, is an important initial step in drug development and relies on sensitive, specific, and robust cell-based assays. Here, we describe a kinetic cellular assay with a fluorescent readout primarily designed to identify receptor-specific antagonists that inhibit the intracellular Ca2+ release evoked upon the activation of the CXC chemokine receptor 4 (CXCR4) by its endogenous ligand, the CXC chemokine ligand 12 (CXCL12)...
February 20, 2018: Journal of Visualized Experiments: JoVE
Ran Tao, Qiang Li, Xiaofei Gao, Lilin Ma
There are a limited number of studies reporting on the expression of G protein-coupled receptor kinase 6 (GRK6) in colorectal carcinoma (CRC). The aim of the present study was to investigate and examine the clinical value of GRK6 expression in human CRC. The expression of the GRK6 protein was determined in CRC tissues (n=83) and in normal colorectal tissues (n=19) by immunohistochemical (IHC) analysis. In addition, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was conducted to investigate GRK6 mRNA levels in matched pairs of cancerous and non-cancerous fresh frozen tissues from 19 patients with CRC...
April 2018: Oncology Letters
Mei-Yi Lu, Syuan-Shao Lu, Shiann-Luen Chang, Fang Liao
CCR6 is a G protein-coupled receptor (GPCR) that recognizes a single chemokine ligand, CCL20 and is primarily expressed by leukocytes. Upon ligand binding, CCR6 activates Gαi heterotrimeric G proteins to induce various potential cellular outcomes through context-specific cell signaling. It is well known that differential phosphorylation of Ser and Thr residues in the C-terminal domains or intracellular loops of GPCRs can generate barcodes that regulate GPCR function by regulating the recruitment of β-arrestins...
2018: Frontiers in Immunology
Marco A Alfonzo-Méndez, Gabriel Carmona-Rosas, David A Hernández-Espinosa, M Teresa Romero-Ávila, J Adolfo García-Sáinz
Human α1D -adrenoceptors (α1D -ARs) are a group of the seven transmembrane-spanning proteins that mediate many of the physiological and pathophysiological actions of adrenaline and noradrenaline. Although it is known that α1D -ARs are phosphoproteins, their specific phosphorylation sites and the kinases involved in their phosphorylation remain largely unknown. Using a combination of in silico analysis, mass spectrometry and site directed mutagenesis, we identified distinct α1D -AR phosphorylation patterns during noradrenaline- or phorbol ester-mediated desensitizations...
March 15, 2018: Biochimica et Biophysica Acta
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