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https://www.readbyqxmd.com/read/28212204/1-2-4-dibromophenyl-3-6-6-trimethyl-1-5-6-7-tetrahydro-4h-indazol-4-one-a-novel-opioid-receptor-agonist-with-less-accompanying-gastrointestinal-dysfunction-than-morphine
#1
Po-Kuan Chao, Shau-Hua Ueng, Li-Chin Ou, Teng-Kuang Yeh, Wan-Ting Chang, Hsiao-Fu Chang, Shu-Chun Chen, Pao-Luh Tao, Ping-Yee Law, Horace H Loh, Ming-Fu Cheng, Jian-Ying Chuang, Chiung-Tong Chen, Chuan Shih, Shiu-Hwa Yeh
BACKGROUND: The authors investigated the pharmacology and signaling pathways of the opioid receptors modulated by compound 1, 1-(2,4-dibromophenyl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one. METHODS: In vitro studies of compound 1 were assessed by using a radioligand-binding assay (n = 3), a cyclic adenosine monophosphate assay (n = 3), a β-arrestin assay (n = 3), an internalization assay (n = 3), and an immunohistochemistry (n = 8). In vivo studies of compound 1 were characterized using a tail-flick test (n = 5 to 6), tail-clip test (n = 7), von Frey hair test (n = 5), and charcoal meal test (n = 5)...
February 17, 2017: Anesthesiology
https://www.readbyqxmd.com/read/28195946/g-protein-coupled-receptor-mediated-transactivation-of-extracellular-proteases
#2
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/28195188/sumo-regulates-the-activity-of-smoothened-and-costal-2-in-drosophila-hedgehog-signaling
#3
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/28182309/propagation-of-the-allosteric-modulation-induced-by-sodium-in-the-%C3%AE-opioid-receptor
#4
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/28181498/arrestin-biased-at1r-agonism-induces-acute-catecholamine-secretion-through-trpc3-coupling
#5
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/28176162/somatostatin-receptor-ligands-in-the-treatment-of-acromegaly
#6
REVIEW
Monica R Gadelha, Luiz Eduardo Wildemberg, Marcello D Bronstein, Federico Gatto, Diego Ferone
First-generation somatostatin receptors ligands (SRL) are the mainstay in the medical treatment of acromegaly, however the percentage of patients controlled with these drugs significantly varies in the different studies. Many factors are involved in the resistance to SRL. In this review, we update the physiology of somatostatin and its receptors (sst), the use of SRL in the treatment of acromegaly and the factors involved in the response to these drugs. The SRL act through interaction with the sst, which up to now have been characterized as five subtypes...
February 7, 2017: Pituitary
https://www.readbyqxmd.com/read/28174117/%C3%AE-arrestin-signalling-and-bias-in-hormone-responsive-gpcrs
#7
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
#8
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
https://www.readbyqxmd.com/read/28167453/the-role-of-%C3%AE-arrestin-2-on-fear-anxious-related-memory-in-a-rat-model-of-post-traumatic-stress-disorder
#9
Jinlan Ding, Fang Han, Lili Wen, Bing Xiao, Yuxiu Shi
BACKGROUND: Post-traumatic stress disorder (PTSD) can be categorised as a disorder of dysregulated fear processing. In the formation and development of PTSD, whether fear/anxious-related memory is regulated by β-arrestin-2, and happened along the signal transduction pathways remains unknown. METHOD: We used single prolonged stress (SPS) as the animal model of PTSD. Next, elevated plus maze tests (EPM) was performed to examine fear/anxious memory- related behaviors...
January 17, 2017: Journal of Affective Disorders
https://www.readbyqxmd.com/read/28160606/discovery-and-pharmacological-characterization-of-succinate-receptor-sucnr1-gpr91-agonists
#10
Pierre Geubelle, Julie Gilissen, Sébastien Dilly, Laurence Poma, Nadine Dupuis, Céline Laschet, Dayana Abboud, Asuka Inoue, François Jouret, Bernard Pirotte, Julien Hanson
BACKGROUND AND PURPOSE: The succinate receptor (SUCNR1 or GPR91) has been described as a metabolic sensor that may be involved in homeostasis. Notwithstanding its implication in important (patho)physiological processes, the function of SUCNR1 has remained elusive because no pharmacological tools were available. We report on the discovery of the first family of synthetic potent agonists. EXPERIMENTAL APPROACH: We screened a library of succinate analogues and analysed their activity on SUCNR1...
February 4, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28153854/sequence-specific-regulation-of-endocytic-lifetimes-modulates-arrestin-mediated-signaling-at-the-%C3%AE-opioid-receptor
#11
Zara Y Weinberg, Amanda S Zajac, Tiffany Phan, Daniel J Shiwarski, Manojkumar A Puthenveedu
Functional selectivity at the μ opioid receptor (μR), a prototypical GPCR that is a physiologically relevant target for endogenous opioid neurotransmitters and analgesics, has been a major focus for drug discovery in the recent past. The cellular mechanisms that mediate functional selectivity, however, are still being fully elucidated. The present work tested the hypothesis that lifetimes of agonist-induced receptor-arrestin clusters at the cell surface controls the magnitude of arrestin signaling, and therefore functional selectivity, on μR...
February 2, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28151698/immunocytochemical-profiling-of-cultured-mouse-primary-retinal-cells
#12
Marina C Zalis, Sebastian Johansson, Ulrica Englund-Johansson
Primary retinal cell cultures and immunocytochemistry are important experimental platforms in ophthalmic research. Translation of retinal cells from their native environment to the in vitro milieu leads to cellular stress, jeopardizing their in vivo phenotype features. Moreover, the specificity and stability of many retinal immunochemical markers are poorly evaluated in retinal cell cultures. Hence, we here evaluated the expression profile of 17 retinal markers, that is, recoverin, rhodopsin, arrestin, Chx10, PKC, DCX, CRALBP, GS, vimentin, TPRV4, RBPMS, Brn3a, β-tubulin III, NeuN, MAP2, GFAP, and synaptophysin...
January 1, 2017: Journal of Histochemistry and Cytochemistry: Official Journal of the Histochemistry Society
https://www.readbyqxmd.com/read/28148497/shear-stress-induces-g%C3%AE-q-11-activation-independent-of-g-protein-coupled-receptor-activation-in-endothelial-cells
#13
Nathaniel G Dela Paz, Benoît Melchior, John A Frangos
Mechanochemical signal transduction occurs when mechanical forces, such as fluid shear stress, are converted into biochemical responses within the cell. The molecular mechanisms by which endothelial cells (ECs) sense/transduce shear stress into biological signals, including the nature of the mechanosensor, are still unclear. G proteins and G protein-coupled receptors (GPCRs) have been postulated independently to mediate mechanotransduction. In this study, we used in situ proximity ligation assay (PLA) to investigate the role of a specific GPCR/Gαq/11 pair in EC shear stress-induced mechanotransduction...
February 1, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/28145434/%C3%AE-arrestin-2-is-an-essential-regulator-of-pancreatic-%C3%AE-cell-function-under-physiological-and-pathophysiological-conditions
#14
Lu Zhu, Joana Almaça, Prasanna K Dadi, Hao Hong, Wataru Sakamoto, Mario Rossi, Regina J Lee, Nicholas C Vierra, Huiyan Lu, Yinghong Cui, Sara M McMillin, Nicole A Perry, Vsevolod V Gurevich, Amy Lee, Bryan Kuo, Richard D Leapman, Franz M Matschinsky, Nicolai M Doliba, Nikhil M Urs, Marc G Caron, David A Jacobson, Alejandro Caicedo, Jürgen Wess
β-arrestins are critical signalling molecules that regulate many fundamental physiological functions including the maintenance of euglycemia and peripheral insulin sensitivity. Here we show that inactivation of the β-arrestin-2 gene, barr2, in β-cells of adult mice greatly impairs insulin release and glucose tolerance in mice fed with a calorie-rich diet. Both glucose and KCl-induced insulin secretion and calcium responses were profoundly reduced in β-arrestin-2 (barr2) deficient β-cells. In human β-cells, barr2 knockdown abolished glucose-induced insulin secretion...
February 1, 2017: Nature Communications
https://www.readbyqxmd.com/read/28142305/effects-of-acute-and-repeated-treatment-with-the-biased-mu-opioid-receptor-agonist-trv130-oliceridine-on-measures-of-antinociception-gastrointestinal-function-and-abuse-liability-in-rodents
#15
Ahmad A Altarifi, Bethany David, Karan H Muchhala, Bruce E Blough, Hamid Akbarali, S Stevens Negus
RATIONALE: TRV130 (oliceridine; N-[(3-methoxythiophen-2-yl)methyl]-2-[(9 R)-9-pyridin-2-yl-6-oxaspiro[4.5]decan-9-yl]ethanamine) is a novel mu opioid receptor (MOR) agonist that preferentially activates G-protein versus β-arrestin signaling pathways coupled to MORs. Prevailing evidence suggests that TRV130 and other G-protein-biased MOR agonists may produce therapeutic analgesic effects with reduced adverse effects compared to existing MOR agonists. OBJECTIVES: This study compared the effects of acute and repeated TRV130 administration on measures of antinociception, gastrointestinal function, and abuse liability in rodents...
January 1, 2017: Journal of Psychopharmacology
https://www.readbyqxmd.com/read/28137936/elabela-toddler-is-an-endogenous-agonist-of-the-apelin-apj-receptor-in-the-adult-cardiovascular-system-and-exogenous-administration-of-the-peptide-compensates-for-the-downregulation-of-its-expression-in-pulmonary-arterial-hypertension
#16
Peiran Yang, Cai Read, Rhoda E Kuc, Guido Buonincontri, Mark Southwood, Rubben Torella, Paul D Upton, Alexi Crosby, Stephen J Sawiak, T Adrian Carpenter, Robert C Glen, Nicholas W Morrell, Janet J Maguire, Anthony P Davenport
BACKGROUND: -Elabela/Toddler (ELA) is a critical cardiac developmental peptide that acts through the G protein-coupled apelin receptor, despite lack of sequence similarity to the established ligand apelin. Our aim was to investigate the receptor pharmacology, expression pattern and in vivo function of ELA peptides in the adult cardiovascular system, to seek evidence for alteration in pulmonary arterial hypertension (PAH) in which apelin signaling is down-regulated, and to demonstrate attenuation of PAH severity with exogenous administration of ELA in a rat model...
January 30, 2017: Circulation
https://www.readbyqxmd.com/read/28137506/gpcr-desensitization-acute-and-prolonged-phases
#17
REVIEW
Sudarshan Rajagopal, Sudha K Shenoy
G protein-coupled receptors (GPCRs) transduce a wide array of extracellular signals and regulate virtually every aspect of physiology. While GPCR signaling is essential, overstimulation can be deleterious, resulting in cellular toxicity or uncontrolled cellular growth. Accordingly, nature has developed a number of mechanisms for limiting GPCR signaling, which are broadly referred to as desensitization, and refer to a decrease in response to repeated or continuous stimulation. Short-term desensitization occurs over minutes, and is primarily associated with β-arrestins preventing G protein interaction with a GPCR...
January 28, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28130548/allosteric-beta-blocker-isolated-from-a-dna-encoded-small-molecule-library
#18
Seungkirl Ahn, Alem W Kahsai, Biswaranjan Pani, Qin-Ting Wang, Shuai Zhao, Alissa L Wall, Ryan T Strachan, Dean P Staus, Laura M Wingler, Lillian D Sun, Justine Sinnaeve, Minjung Choi, Ted Cho, Thomas T Xu, Gwenn M Hansen, Michael B Burnett, Jane E Lamerdin, Daniel L Bassoni, Bryant J Gavino, Gitte Husemoen, Eva K Olsen, Thomas Franch, Stefano Costanzi, Xin Chen, Robert J Lefkowitz
The β2-adrenergic receptor (β2AR) has been a model system for understanding regulatory mechanisms of G-protein-coupled receptor (GPCR) actions and plays a significant role in cardiovascular and pulmonary diseases. Because all known β-adrenergic receptor drugs target the orthosteric binding site of the receptor, we set out to isolate allosteric ligands for this receptor by panning DNA-encoded small-molecule libraries comprising 190 million distinct compounds against purified human β2AR. Here, we report the discovery of a small-molecule negative allosteric modulator (antagonist), compound 15 [([4-((2S)-3-(((S)-3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)amino)-2-(2-cyclohexyl-2-phenylacetamido)-3-oxopropyl)benzamide], exhibiting a unique chemotype and low micromolar affinity for the β2AR...
January 27, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28126849/targeting-a-par4-carboxyl-terminal-motif-to-regulate-platelet-function
#19
Rithwik Ramachandran, Koichiro Mihara, Pierre Thibeault, Christina M Vanderboor, Bjoern Petri, Mahmoud Saifeddine, Michel Bouvier, Morley D Hollenberg
Thrombin initiates human platelet aggregation by coordinately activating proteinase activated receptors (PARs)-1 and -4. However, targeting PAR1 with an orthostatic tethered ligand binding site antagonist results in bleeding, possibly due to the important role of PAR1 activation on cells other than platelets. Because of its more restricted tissue expression profile, we have therefore turned to PAR4 as an antiplatelet target. We have identified an intracellular PAR4 C-terminal motif that regulates calcium signaling and β-arrestin interactions...
January 26, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28125336/new-insights-into-mechanisms-of-nuclear-translocation-of-g-protein-coupled-receptors
#20
Vikrant K Bhosle, José Carlos Rivera, Sylvain Chemtob
The G-protein coupled receptor (GPCR) signaling was long believed to involve activation of receptor exclusively at the cell surface, followed by its binding to heterotrimeric G-proteins and arrestins to trigger various intracellular signaling cascades, and termination of signaling by internalization of the receptor. It is now accepted that many GPCRs continue to signal after internalization in the endosomes. Since the breakthrough discoveries of nuclear binding sites for their ligands in 1980s, several GPCRs have been detected at cell nuclei...
January 26, 2017: Small GTPases
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