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https://www.readbyqxmd.com/read/28448471/regulation-of-g-protein-coupled-receptors-by-ubiquitination
#1
REVIEW
Kamila Skieterska, Pieter Rondou, Kathleen Van Craenenbroeck
G protein-coupled receptors (GPCRs) comprise the largest family of membrane receptors that control many cellular processes and consequently often serve as drug targets. These receptors undergo a strict regulation by mechanisms such as internalization and desensitization, which are strongly influenced by posttranslational modifications. Ubiquitination is a posttranslational modification with a broad range of functions that is currently gaining increased appreciation as a regulator of GPCR activity. The role of ubiquitination in directing GPCRs for lysosomal degradation has already been well-established...
April 27, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28448021/detection-of-ligand-activated-g-protein-coupled-receptor-internalization-by-confocal-microscopy
#2
Jingwen Yang, Yunjun Yan, Xiaowei Xiang, Yuchao Xu, Naiming Zhou, Tianming Wang
Confocal laser scanning microscopy (CLSM) is an optical imaging technique for high-contrast imaging. It is a powerful approach to visualize fluorescent fusion proteins, such as green fluorescent protein (GFP), to determine their expression, localization, and function. The subcellular localization of target proteins is important for identification, characterization, and functional analyses. Internalization is one of the predominant mechanisms controlling G protein-coupled receptor (GPCR) signaling to ensure the appropriate cellular responses to stimuli...
April 9, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28438833/g-protein-gi1-exhibits-basal-coupling-but-not-preassembly-with-g-protein-coupled-receptors
#3
Alexey Bondar, Josef Lazar
The Gi/o protein family transduces signals from a diverse group of G protein-coupled receptors (GPCRs). The observed specificity of Gi/o-GPCR coupling and high rate of Gi/o signal transduction have been hypothesized to be enabled by existence of stable associates between Gi/o proteins and their cognate GPCRs in the inactive state (Gi/o-GPCR preassembly). To test this hypothesis, we applied the recently developed technique of two-photon polarization microscopy (2PPM) to Gαi1 subunits labeled with fluorescent proteins and four GPCRs (the α2A-adrenergic receptor (α2A-AR), γ-aminobutyric acid receptor B (GABAB), cannabinoid receptor type 1 (CB1R) and dopamine receptor type 2 (D2R))...
April 24, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28431242/structural-and-functional-analysis-of-a-%C3%AE-2-adrenergic-receptor-complex-with-grk5
#4
Konstantin E Komolov, Yang Du, Nguyen Minh Duc, Robin M Betz, João P G L M Rodrigues, Ryan D Leib, Dhabaleswar Patra, Georgios Skiniotis, Christopher M Adams, Ron O Dror, Ka Young Chung, Brian K Kobilka, Jeffrey L Benovic
The phosphorylation of agonist-occupied G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) functions to turn off G-protein signaling and turn on arrestin-mediated signaling. While a structural understanding of GPCR/G-protein and GPCR/arrestin complexes has emerged in recent years, the molecular architecture of a GPCR/GRK complex remains poorly defined. We used a comprehensive integrated approach of cross-linking, hydrogen-deuterium exchange mass spectrometry (MS), electron microscopy, mutagenesis, molecular dynamics simulations, and computational docking to analyze GRK5 interaction with the β2-adrenergic receptor (β2AR)...
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28427097/systematic-quantification-of-gpcr-camp-controlled-protein-kinase-a-interactions
#5
O Torres-Quesada, R Röck, E Stefan
The diffusible second messenger cyclic AMP (cAMP) originates from multiple G protein-coupled receptor (GPCR) cascades activating the intracellular key effector protein kinase A (PKA). Spatially and temporally restricted cAMP-fluxes are directly sensed by macromolecular PKA complexes. The consequences are alterations of molecular interactions, which lead to activation of compartmentalized PKA phosphotransferase activities, regulating a vast array of cellular functions. To decode cell-type and cell-compartment specific PKA functions, the spatio-temporal dynamics of small molecule:protein interactions, protein:protein interactions (PPIs), cAMP-mobilization, and phosphotransferase activities need to be determined directly in the appropriate cellular context...
April 2017: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
https://www.readbyqxmd.com/read/28424220/gababr-induced-egfr-transactivation-promotes-migration-of-human-prostate-cancer-cells
#6
Shuai Xia, Cong He, Yini Zhu, Suyun Wang, Huiping Li, Zhongling Zhang, Xinnong Jiang, Jianfeng Liu
G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) act in concert to regulate cell growth, proliferation, survival, and migration. Metabotropic GABAB receptor (GABABR) is the GPCR for the main inhibitory neurotransmitter GABA in the central nervous system. Increased expression of GABABR has been detected in human cancer tissues and cancer cell lines, but the role of GABABR in these cells is controversial and the underlying mechanism remains poorly understood. Here, we investigated whether GABABR hijacks RTK signaling to modulate the fates of human prostate cancer cells...
April 19, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28421075/activation-of-adhesion-gpcr-emr2-adgre2-induces-macrophage-differentiation-and-inflammatory-responses-via-g%C3%AE-16-akt-mapk-nf-%C3%AE%C2%BAb-signaling-pathways
#7
Kuan-Yu I, Yi-Shu Huang, Ching-Hsun Hu, Wen-Yi Tseng, Chia-Hsin Cheng, Martin Stacey, Siamon Gordon, Gin-Wen Chang, Hsi-Hsien Lin
EMR2/ADGRE2 is a human myeloid-restricted adhesion G protein-coupled receptor critically implicated in vibratory urticaria, a rare type of allergy caused by vibration-induced mast cell activation. In addition, EMR2 is also highly expressed by monocyte/macrophages and has been linked to neutrophil migration and activation. Despite these findings, little is known of EMR2-mediated signaling and its role in myeloid biology. In this report, we show that activation of EMR2 via a receptor-specific monoclonal antibody promotes the differentiation of human THP-1 monocytic cell line and induces the expression of pro-inflammatory mediators, including IL-8, TNF-α, and MMP-9...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28417881/understanding-gpcr-signaling-in-the-brain-the-path-to-cns-drug-discovery
#8
EDITORIAL
David Chatenet, Terence E Hébert
No abstract text is available yet for this article.
February 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28416805/a-new-inhibitor-of-the-%C3%AE-arrestin-ap2-endocytic-complex-reveals-interplay-between-gpcr-internalization-and-signalling
#9
Alexandre Beautrait, Justine S Paradis, Brandon Zimmerman, Jenna Giubilaro, Ljiljana Nikolajev, Sylvain Armando, Hiroyuki Kobayashi, Lama Yamani, Yoon Namkung, Franziska M Heydenreich, Etienne Khoury, Martin Audet, Philippe P Roux, Dmitry B Veprintsev, Stéphane A Laporte, Michel Bouvier
In addition to G protein-coupled receptor (GPCR) desensitization and endocytosis, β-arrestin recruitment to ligand-stimulated GPCRs promotes non-canonical signalling cascades. Distinguishing the respective contributions of β-arrestin recruitment to the receptor and β-arrestin-promoted endocytosis in propagating receptor signalling has been limited by the lack of selective analytical tools. Here, using a combination of virtual screening and cell-based assays, we have identified a small molecule that selectively inhibits the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP2 without interfering with the formation of receptor/β-arrestin complexes...
April 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28412414/endothelin-1-promotes-hypertrophic-remodelling-of-cardiac-myocytes-by-activating-sustained-signalling-and-transcription-downstream-of-endothelin-type-a-receptors
#10
Caroline R Archer, Emma L Robinson, Faye M Drawnel, H Llewelyn Roderick
G-protein coupled receptor (GPCR) mediated activation of the MAPK signalling cascade is a key pathway in the induction of hypertrophic remodelling of the heart - a response to pathological cues including hypertension and myocardial infarction. While levels of pro-hypertrophic hormone agonists of GPCRs increase during periods of greater workload to enhance cardiac output, hypertrophy does not necessarily result. Here we investigated the relationship between the duration of exposure to the pro-hypertrophic GPCR agonist endothelin-1 (ET-1) and the induction of hypertrophic remodelling in neonatal rat ventricular myocytes (NRVM) and in the adult rat heart in vivo...
April 13, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28412413/activation-of-muscarinic-receptors-prevents-tnf-%C3%AE-mediated-intestinal-epithelial-barrier-disruption-through-p38-mapk
#11
Junsuke Uwada, Takashi Yazawa, Md Tariqul Islam, Md Rafiqul Islam Khan, Susanne M Krug, Michael Fromm, Shin-Ichiro Karaki, Yuichi Suzuki, Atsukazu Kuwahara, Hatsumi Yoshiki, Kiyonao Sada, Ikunobu Muramatsu, Takanobu Taniguchi
Intestinal epithelial cells form a tight barrier to act as selective physical barriers, repelling hostile substances. Tumor necrosis factor-α (TNF-α) is a well characterized pro-inflammatory cytokine which can compromise intestinal barrier function and the suppression of TNF-α function is important for treatment of inflammatory bowel disease (IBD). In this study, we investigated the contribution of G-protein-coupled receptor (GPCR)-induced signalling pathways to the maintenance of epithelial barrier function...
April 12, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28407060/role-of-osteoblast-gi-signaling-in-age-related-bone-loss-in-female-mice
#12
Susan M Millard, Liping Wang, Lalita Wattanachanya, Dylan O'Carroll, Aaron J Fields, Joyce Pang, Galateia Kazakia, Jeffrey C Lotz, Robert A Nissenson
Age-related bone loss is an important risk factor for fractures in the elderly, resulting from an imbalance in bone remodeling mainly due to decreased bone formation. We have previously demonstrated that endogenous G protein coupled receptor (GPCR)-driven Gi signaling in osteoblasts (Obs) restrains bone formation in mice during growth. Here, we launched a longitudinal study to test the hypothesis that Gi signaling in Obs restrains bone formation in aging mice, thereby promoting bone loss. Our approach was to block Gi signaling in maturing Obs by the induced expression of the catalytic subunit of pertussis toxin (PTX) after the achievement of peak bone mass...
April 12, 2017: Endocrinology
https://www.readbyqxmd.com/read/28402104/hydrogen-deuterium-exchange-mass-spectrometry-of-human-green-opsin-reveals-a-conserved-pro-pro-motif-in-extracellular-loop-2-of-monostable-visual-g-protein-coupled-receptors
#13
Lukas Hofmann, Nathan S Alexander, Wenyu Sun, Jianye Zhang, Tivadar Orban, Krzysztof Palczewski
Opsins comprise the protein component of light sensitive G protein-coupled receptors (GPCRs) in the retina of the eye that are responsible for the transduction of light into a biochemical signal. Here, we used hydrogen/deuterium (H/D) exchange coupled with mass spectrometry to map conformational changes in green cone opsin upon light activation. We then compared these findings with those reported for rhodopsin. The extent of H/D exchange in green cone opsin was greater than in rhodopsin in the dark and bleached states, suggesting a higher structural heterogeneity for green cone opsin...
April 21, 2017: Biochemistry
https://www.readbyqxmd.com/read/28396447/dual-optical-control-and-mechanistic-insights-into-photoswitchable-group-ii-and-iii-metabotropic-glutamate-receptors
#14
Joshua Levitz, Johannes Broichhagen, Philipp Leippe, David Konrad, Dirk Trauner, Ehud Y Isacoff
G protein-coupled receptor (GPCR) signaling occurs in complex spatiotemporal patterns that are difficult to probe using standard pharmacological and genetic approaches. A powerful approach for dissecting GPCRs is to use light-controlled pharmacological agents that are tethered covalently and specifically to genetically engineered receptors. However, deficits in our understanding of the mechanism of such photoswitches have limited application of this approach and its extension to other GPCRs. In this study, we have harnessed the power of bioorthogonal tethering to SNAP and CLIP protein tags to create a family of light-gated metabotropic glutamate receptors (mGluRs)...
April 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28390954/the-effects-of-ramps-upon-cell-signalling
#15
Sarah J Routledge, Graham Ladds, David R Poyner
G protein-coupled receptors (GPCRs) play a vital role in signal transduction. It is now clear that numerous other molecules within the cell and at the cell surface interact with GPCRs to modulate their signalling properties. Receptor activity modifying proteins (RAMPs) are a group of single transmembrane domain proteins which have been predominantly demonstrated to interact with Family B GPCRs, but interactions with Family A and C receptors have recently begun to emerge. These interactions can influence cell surface expression, ligand binding preferences and G protein-coupling, thus modulating GPCR signal transduction...
April 5, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28389415/g-protein-coupled-receptor-kinase-2-grk2-as-an-integrative-signalling-node-in-the-regulation-of-cardiovascular-function-and-metabolic-homeostasis
#16
REVIEW
Federico Mayor, Marta Cruces-Sande, Alba C Arcones, Rocío Vila-Bedmar, Ana M Briones, Mercedes Salaices, Cristina Murga
G protein-coupled receptor kinase 2 (GRK2) is emerging as a pivotal signalling hub able to integrate different transduction cascades. This ability appears to underlie its central role in different physiological and pathological conditions. Key mediators of cardiovascular function (such as catecholamines or angiotensin II) and components of the systemic milieu altered in insulin resistance conditions converge in increasing GRK2 levels in diverse cardiovascular cell types. In turn, GRK2 would simultaneously modulate several cardiovascular regulatory pathways, including GPCR and insulin signalling cascades, NO bioavailability and mitochondrial function...
April 4, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28388415/multidimensional-tracking-of-gpcr-signaling-via-peroxidase-catalyzed-proximity-labeling
#17
Jaeho Paek, Marian Kalocsay, Dean P Staus, Laura Wingler, Roberta Pascolutti, Joao A Paulo, Steven P Gygi, Andrew C Kruse
G-protein-coupled receptors (GPCRs) play critical roles in regulating physiological processes ranging from neurotransmission to cardiovascular function. Current methods for tracking GPCR signaling suffer from low throughput, modification or overexpression of effector proteins, and low temporal resolution. Here, we show that peroxidase-catalyzed proximity labeling can be combined with isobaric tagging and mass spectrometry to enable quantitative, time-resolved measurement of GPCR agonist response in living cells...
April 6, 2017: Cell
https://www.readbyqxmd.com/read/28386636/dynamic-monitoring-of-gi-o-protein-mediated-decreases-of-intracellular-camp-by-fret-based-epac-sensors
#18
Ursula Storch, Julie Straub, Serap Erdogmus, Thomas Gudermann, Michael Mederos Y Schnitzler
Analysis of G-protein-coupled receptor (GPCR) signaling, in particular of the second messenger cAMP that is tightly controlled by Gs- and Gi/o-proteins, is a central issue in biomedical research. The classical biochemical method to monitor increases in intracellular cAMP concentrations consists of a radioactive multicellular assay, which is well established, highly sensitive, and reproducible, but precludes continuous spatial and temporal assessment of cAMP levels in single living cells. For this purpose, Förster resonance energy transfer (FRET)-based Epac cAMP sensors are well suitable...
April 6, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28385695/transient-receptor-potential-ion-channel-function-in-sensory-transduction-and-cellular-signaling-cascades-underlying-visceral-hypersensitivity
#19
Dafne Balemans, Guy E Boeckxstaens, Karel Talavera, Mira M Wouters
Visceral hypersensitivity is an important mechanism underlying increased abdominal pain perception in functional gastrointestinal disorders (FGID) including functional dyspepsia, irritable bowel syndrome (IBS) and inflammatory bowel disease in remission. Although the exact pathophysiological mechanisms are poorly understood, recent studies described upregulation and altered functions of nociceptors and their signaling pathways in aberrant visceral nociception, in particular the transient receptor potential (TRP) channel family...
April 6, 2017: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/28382133/the-controversial-role-of-phospholipase-c-epsilon-plc%C3%AE%C2%B5-in-cancer-development-and-progression
#20
REVIEW
Anna Tyutyunnykova, Gennady Telegeev, Anna Dubrovska
The phospholipase C (PLC) enzymes are important regulators of membrane phospholipid metabolism. PLC proteins can be activated by the receptor tyrosine kinases (RTK) or G-protein coupled receptors (GPCR) in response to the different extracellular stimuli including hormones and growth factors. Activated PLC enzymes hydrolyze phosphoinositides to increase the intracellular level of Ca(2+) and produce diacylglycerol, which are important mediators of the intracellular signaling transduction. PLC family includes 13 isozymes belonging to 6 subfamilies according to their domain structures and functions...
2017: Journal of Cancer
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