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https://www.readbyqxmd.com/read/28213525/conformational-profiling-of-the-at1-angiotensin-ii-receptor-reflects-biased-agonism-g-protein-coupling-and-cellular-context
#1
Dominic Devost, Rory Sleno, Darlaine Petrin, Alice Zhang, Yuji Shinjo, Rakan Okde, Junken Aoki, Asuka Inoue, Terence E Hebert
Here, we report the design and use of GPCR-based biosensors to monitor ligand-mediated conformational changes in receptors in intact cells. These biosensors use Bioluminescence Resonance Energy Transfer (BRET) with Renilla luciferase (RlucII) as an energy donor, placed at the distal end of the receptor C-tail and the small fluorescent molecule FlAsH, as an energy acceptor, its binding site inserted at different positions throughout the intracellular loops and carboxy-terminal tail of the angiotensin II type I receptor (AT1R)...
February 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28213524/g-protein-coupled-receptor-kinase-2-grk-2-regulates-serotonin-metabolism-through-the-monoamine-oxidase-amx-2-in-caenorhabditis-elegans
#2
Jianjun Wang, Jiansong Luo, Dipendra K Aryal, William C Wetzel, Richard Nass, Jeffrey L Benovic
G protein-coupled receptors (GPCRs) regulate many animal behaviors. GPCR signaling is mediated by agonist-promoted interactions of GPCRs with heterotrimeric G proteins, GPCR kinases (GRKs) and arrestins. To further elucidate the role of GRKs in regulating GPCR-mediated behaviors, we utilized the genetic model system Caenorhabditis elegans. Our studies demonstrate that grk-2 loss-of-function strains are egg-laying defective and contain low levels of serotonin (5-HT) and high levels of the 5-HT metabolite 5-hydroxyindole acetic acid (5-HIAA)...
February 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28212842/pathophysiological-consequences-of-receptor-mistraffic-tales-from-the-platelet-p2y12-receptor
#3
Margaret R Cunningham, Riyaad Aungraheeta, Stuart J Mundell
Genetic variations in G protein-coupled receptor (GPCR) genes can disrupt receptor function in a wide variety of human genetic diseases, including platelet bleeding disorders. Platelets are critical for haemostasis with inappropriate platelet activation leading to the development of arterial thrombosis, which can result in heart attack and stroke whilst decreased platelet activity is associated with an increased risk of bleeding. GPCRs expressed on the surface of platelets play key roles in regulating platelet activity and therefore function...
February 14, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28209512/n-glycan-dependent-cell-surface-expression-of-the-p2y2-receptor-and-n-glycan-independent-distribution-to-lipid-rafts
#4
Tetsuto Nakagawa, Chihiro Takahashi, Hitomi Matsuzaki, Shohei Takeyama, Shinpei Sato, Ayaka Sato, Yoshiyuki Kuroda, Hideyoshi Higashi
P2Y2 receptor (P2Y2R) is a G-protein-coupled receptor (GPCR) couples with Gαq/11 and is stimulated by ATP and UTP. P2Y2R is involved in pain, proinflammatory changes, and blood pressure control. Some GPCRs are localized in lipid rafts for interaction with other signaling molecules. In this study, we prepared N-glycan-deficient mutants by mutating the two consensus Asn residues for N-glycosylation to Gln to examine intracellular localization and association with lipid rafts. Western blotting of the wild type (WT) protein and mutants (N9Q, N13Q, N9Q/N13Q) in COS-7 cells showed that both Asn residues were glycosylated in the WT...
February 13, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28196832/gpr55-a-new-promising-target-for-metabolism
#5
Eva Tuduri, Monica Imbernon, Rene Bautista, Marta Tojo, Johan Fernø, Carlos Diéguez, Rubén Nogueiras
GPR55 is a G-protein coupled receptor (GPCR) that has been identified as a new cannabinoid receptor. Given the wide localization of GPR55 in brain and peripheral tissues, this receptor has emerged as a regulator of multiple biological actions. Lysophosphatidylinositol (LPI) is generally accepted as the endogenous ligand of GPR55. In this review, we will focus on the role of GPR55 in energy balance and glucose metabolism. We will summarize its actions on feeding, nutrient partitioning, gastrointestinal motility and insulin secretion in preclinical models and the scarce data available in humans...
February 14, 2017: Journal of Molecular Endocrinology
https://www.readbyqxmd.com/read/28195946/g-protein-coupled-receptor-mediated-transactivation-of-extracellular-proteases
#6
Allison E Schafer, Burns C Blaxall
G protein-coupled receptors (GPCRs) comprise the largest family of receptors in humans. Traditional activation of GPCRs involves binding of a ligand to the receptor, activation of heterotrimeric G proteins and induction of subsequent signaling molecules. It is now known that GPCR signaling occurs through G protein-independent pathways including signaling through β-arrestin as well as transactivation of other receptor types. Generally, transactivation occurs when activation of one receptor leads to the activation of another receptor(s)...
February 13, 2017: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/28195232/hematopoietic-pannexin-1-function-is-critical-for-neuropathic-pain
#7
Janelle L Weaver, Sanja Arandjelovic, Gregory Brown, Suresh K Mendu, Michael S Schappe, Monica W Buckley, Yu-Hsin Chiu, Shaofang Shu, Jin K Kim, Joyce Chung, Julia Krupa, Vesna Jevtovic-Todorovic, Bimal N Desai, Kodi S Ravichandran, Douglas A Bayliss
Neuropathic pain symptoms respond poorly to available therapeutics, with most treated patients reporting unrelieved pain and significant impairment in daily life. Here, we show that Pannexin 1 (Panx1) in hematopoietic cells is required for pain-like responses following nerve injury in mice, and a potential therapeutic target. Panx1 knockout mice (Panx1(-/-)) were protected from hypersensitivity in two sciatic nerve injury models. Bone marrow transplantation studies show that expression of functional Panx1 in hematopoietic cells is necessary for mechanical hypersensitivity following nerve injury...
February 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28195188/sumo-regulates-the-activity-of-smoothened-and-costal-2-in-drosophila-hedgehog-signaling
#8
Jie Zhang, Yajuan Liu, Kai Jiang, Jianhang Jia
In Hedgehog (Hh) signaling, the GPCR-family protein Smoothened (Smo) acts as a signal transducer that is regulated by phosphorylation and ubiquitination, which ultimately change the cell surface accumulation of Smo. However, it is not clear whether Smo is regulated by other post-translational modifications, such as sumoylation. Here, we demonstrate that knockdown of the small ubiquitin-related modifier (SUMO) pathway components Ubc9 (a SUMO-conjugating enzyme E2), PIAS (a SUMO-protein ligase E3), and Smt3 (the SUMO isoform in Drosophila) by RNAi prevents Smo accumulation and alters Smo activity in the wing...
February 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28188824/the-g-protein-coupled-receptor-n-terminus-and-receptor-signalling-n-tering-a-new-era
#9
REVIEW
James L J Coleman, Tony Ngo, Nicola J Smith
G protein-coupled receptors (GPCRs) are a vast family of membrane-traversing proteins, essential to the ability of eukaryotic life to detect, and mount an intracellular response to, a diverse range of extracellular stimuli. GPCRs have evolved with archetypal features including an extracellular N-terminus and intracellular C-terminus that flank a transmembrane structure of seven sequential helices joined by intracellular and extracellular loops. These structural domains contribute to the ability of a GPCR to be correctly synthesised and inserted into the cell membrane, to interact with its cognate ligand(s) and to couple with signal-transducing heterotrimeric G proteins, allowing the activated receptor to selectively modulate a number of signalling cascades...
February 8, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28183248/new-horizons-on-molecular-pharmacology-applied-to-drug-discovery-when-resonance-overcomes-radioligand-binding
#10
Larissa Pernomian, Mayara Santos Gomes, Josimar Moreira Dornelas, Carlos Henrique Tomich de Paula da Silva, Jaoaquín María Campos Rosa, Cristina Ribeiro De Barros Cardoso
One of the cornerstones of rational drug development is the measurement of molecular parameters derived from ligand-receptor interaction, which guides therapeutic windows definition. Over the last decades, radioligand binding has provided valuable contributions in this field as key method for such purposes. However, its limitations spurred the development of more exquisite techniques for determining such parameters. For instance, safety risks related to radioactivity waste, expensive and controlled disposal of radioisotopes, radiotracer separation-dependence for affinity analysis, and one-site mathematical models-based fitting of data make radioligand binding a suboptimal approach in providing measures of actual affinity conformations from ligands and G protein-coupled receptors (GPCR)...
February 8, 2017: Current Radiopharmaceuticals
https://www.readbyqxmd.com/read/28183242/decoding-corticotropin-releasing-factor-receptor-type-1-crystal-structures
#11
Andrew S Doré, Andrea Bortolato, Kaspar Hollenstein, Robert K Y Cheng, Randy J Read, Fiona H Marshall
The structural analysis of class B G protein-coupled receptors (GPCR), cell surface proteins responding to peptide hormones, has until recently been restricted to the extracellular domain (ECD). Corticotropin-releasing factor receptor type 1 (CRF1R) is a class B receptor mediating stress response and also considered a drug target for depression and anxiety. Here we report the crystal structure of the transmembrane domain of human CRF1R in complex with the small-molecule antagonist CP-376395 in a hexagonal setting with translational non-crystallographic symmetry...
January 10, 2017: Current Molecular Pharmacology
https://www.readbyqxmd.com/read/28182309/propagation-of-the-allosteric-modulation-induced-by-sodium-in-the-%C3%AE-opioid-receptor
#12
Xianqiang Sun, Genevieve Laroche, Xu Wang, Hans Ågren, Greg Bowman, Patrick M Giguère, Yaoquan Tu
Allosteric sodium in the helix bundle of a G protein-coupled receptor (GPCR) can modulate the receptor activation on the intracellular side. This phenomenon has confounded the GPCR community for decades. In this work, we present a theoretical model that reveals the mechanism of the allosteric modulation induced by sodium in the δ opioid receptor. We found that the allosteric sodium ion exploits a distinct conformation of the key residue Trp2746.48 to propagate the modulation to helixes 5 and 6, which further transmits along the helixes and regulates their positions on the intracellular side...
February 9, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28181555/determination-of-biological-activity-of-gonadotropins-hcg-and-fsh-by-f%C3%A3-rster-resonance-energy-transfer-based-biosensors
#13
Olga Mazina, Anni Allikalt, Juha S Tapanainen, Andres Salumets, Ago Rinken
Determination of biological activity of gonadotropin hormones is essential in reproductive medicine and pharmaceutical manufacturing of the hormonal preparations. The aim of the study was to adopt a G-protein coupled receptor (GPCR)-mediated signal transduction pathway based assay for quantification of biological activity of gonadotropins. We focussed on studying human chorionic gonadotropin (hCG) and follicle-stimulating hormone (FSH), as these hormones are widely used in clinical practice. Receptor-specific changes in cellular cyclic adenosine monophosphate (cAMP, second messenger in GPCR signalling) were monitored by a Förster resonance energy transfer (FRET) biosensor protein (T)Epac(VV) in living cells upon activation of the relevant gonadotropin receptor...
February 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28181498/arrestin-biased-at1r-agonism-induces-acute-catecholamine-secretion-through-trpc3-coupling
#14
Chun-Hua Liu, Zheng Gong, Zong-Lai Liang, Zhi-Xin Liu, Fan Yang, Yu-Jing Sun, Ming-Liang Ma, Yi-Jing Wang, Chao-Ran Ji, Yu-Hong Wang, Mei-Jie Wang, Fu-Ai Cui, Amy Lin, Wen-Shuai Zheng, Dong-Fang He, Chang-Xiu Qu, Peng Xiao, Chuan-Yong Liu, Alex R B Thomsen, Thomas Joseph Cahill, Alem W Kahsai, Fan Yi, Kun-Hong Xiao, Tian Xue, Zhuan Zhou, Xiao Yu, Jin-Peng Sun
Acute hormone secretion triggered by G protein-coupled receptor (GPCR) activation underlies many fundamental physiological processes. GPCR signalling is negatively regulated by β-arrestins, adaptor molecules that also activate different intracellular signalling pathways. Here we reveal that TRV120027, a β-arrestin-1-biased agonist of the angiotensin II receptor type 1 (AT1R), stimulates acute catecholamine secretion through coupling with the transient receptor potential cation channel subfamily C 3 (TRPC3)...
February 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28179879/cannabinoid-receptors-modulate-neuronal-morphology-and-ankyring-density-at-the-axon-initial-segment
#15
Mónica Tapia, Ana Dominguez, Wei Zhang, Ana Del Puerto, María Ciorraga, María José Benitez, Carmen Guaza, Juan José Garrido
Neuronal polarization underlies the ability of neurons to integrate and transmit information. This process begins early in development with axon outgrowth, followed by dendritic growth and subsequent maturation. In between these two steps, the axon initial segment (AIS), a subcellular domain crucial for generating action potentials (APs) and maintaining the morphological and functional polarization, starts to develop. However, the cellular/molecular mechanisms and receptors involved in AIS initial development and maturation are mostly unknown...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28179123/spinal-or-supraspinal-phosphorylation-deficiency-at-the-mor-c-terminus-does-not-affect-morphine-tolerance-in-vivo
#16
Cherkaouia Kibaly, Hong-Yiou Lin, Horace H Loh, Ping-Yee Law
The development of tolerance to morphine, one of the most potent analgesics, in the management of chronic pain is a significant clinical problem and its mechanisms are poorly understood. Morphine exerts its pharmacological effects via the μ-opioid receptor (MOR). Tolerance is highly connected to G-protein-coupled receptors (GPCR) phosphorylation and desensitization increase. Because morphine desensitization previously has been shown to be MOR phosphorylation- and ß-arrestin2-independent (in contrast to agonists such as fentanyl), we examined the contribution of phosphorylation of the entire C-terminus to the development of antinociceptive tolerance to the partial (morphine) and full (fentanyl) MOR agonists in vivo...
February 4, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28174684/sucralose-activates-an-erk1-2-ribosomal-protein-s6-signaling-axis
#17
Marcy L Guerra, Michael A Kalwat, Kathleen McGlynn, Melanie H Cobb
The sweetener sucralose can signal through its GPCR receptor to induce insulin secretion from pancreatic β cells, but the downstream signaling pathways involved are not well-understood. Here we measure responses to sucralose, glucagon-like peptide 1, and amino acids in MIN6 β cells. Our data suggest a signaling axis, whereby sucralose induces calcium and cAMP, activation of ERK1/2, and site-specific phosphorylation of ribosomal protein S6. Interestingly, sucralose acted independently of mTORC1 or ribosomal S6 kinase (RSK)...
February 2017: FEBS Open Bio
https://www.readbyqxmd.com/read/28174517/a-practical-guide-to-approaching-biased-agonism-at-g-protein-coupled-receptors
#18
Jaimee Gundry, Rachel Glenn, Priya Alagesan, Sudarshan Rajagopal
Biased agonism, the ability of a receptor to differentially activate downstream signaling pathways depending on binding of a "biased" agonist compared to a "balanced" agonist, is a well-established paradigm for G protein-coupled receptor (GPCR) signaling. Biased agonists have the promise to act as smarter drugs by specifically targeting pathogenic or therapeutic signaling pathways while avoiding others that could lead to side effects. A number of biased agonists targeting a wide array of GPCRs have been described, primarily based on their signaling in pharmacological assays...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28174117/%C3%AE-arrestin-signalling-and-bias-in-hormone-responsive-gpcrs
#19
Eric Reiter, Mohammed Akli Ayoub, Lucie P Pellissier, Flavie Landomiel, Astrid Musnier, Aurélie Tréfier, Jorge Gandia, Francesco De Pascali, Shifa Tahir, Romain Yvinec, Gilles Bruneau, Anne Poupon, Pascale Crépieux
G protein-coupled receptors (GPCRs) play crucial roles in the ability of target organs to respond to hormonal cues. GPCRs' activation mechanisms have long been considered as a two-state process connecting the agonist-bound receptor to heterotrimeric G proteins. This view is now challenged as mounting evidence point to GPCRs being connected to large arrays of transduction mechanisms involving heterotrimeric G proteins as well as other players. Amongst the G protein-independent transduction mechanisms, those elicited by β-arrestins upon their recruitment to the active receptors are by far the best characterized and apply to most GPCRs...
February 4, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28169830/phosphorylation-of-%C3%AE-arrestin-2-at-thr-383-by-mek-underlies-%C3%AE-arrestin-dependent-activation-of-erk1-2-by-gpcrs
#20
Elisabeth Cassier, Nathalie Gallay, Thomas Bourquard, Sylvie Claeysen, Joël Bockaert, Pascale Crépieux, Anne Poupon, Eric Reiter, Philippe Marin, Franck Vandermoere
In addition to their role in desensitization and internalization of G protein-coupled receptors (GPCRs), β-arrestins are essential scaffolds linking GPCRs to Erk1/2 signaling. However, their role in GPCR-operated Erk1/2 activation differs between GPCRs and the underlying mechanism remains poorly characterized. Here, we show that activation of serotonin 5-HT2C receptors, which engage Erk1/2 pathway via a β-arrestin-dependent mechanism, promotes MEK-dependent β-arrestin 2 phosphorylation at Thr(383), a necessary step for Erk recruitment to the receptor/β-arrestin complex and Erk activation...
February 7, 2017: ELife
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