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https://www.readbyqxmd.com/read/28341345/the-signaling-signature-of-the-neurotensin-type-1-receptor-with-endogenous-ligands
#1
Élie Besserer-Offroy, Rebecca L Brouillette, Sandrine Lavenus, Ulrike Froehlich, Andrea Brumwell, Alexandre Murza, Jean-Michel Longpré, Éric Marsault, Michel Grandbois, Philippe Sarret, Richard Leduc
The human neurotensin 1 receptor (hNTS1) is a G protein-coupled receptor involved in many physiological functions, including analgesia, hypothermia, and hypotension. To gain a better understanding of which signaling pathways or combination of pathways are linked to NTS1 activation and function, we investigated the ability of activated hNTS1, which was stably expressed by CHO-K1 cells, to directly engage G proteins, activate second messenger cascades and recruit β-arrestins. Using BRET-based biosensors, we found that neurotensin (NT), NT(8-13) and neuromedin N (NN) activated the Gαq-, Gαi1-, GαoA-, and Gα13-protein signaling pathways as well as the recruitment of β-arrestins 1 and 2...
March 21, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28339772/heterologous-desensitization-of-cardiac-%C3%AE-adrenergic-signal-via-hormone-induced-%C3%AE-ar-arrestin-pde4-complexes
#2
Qian Shi, Minghui Li, Delphine Mika, Qin Fu, Sungjin Kim, Jason Phan, Ao Shen, Gregoire Vandecasteele, Yang K Xiang
Aims: Cardiac β-adrenergic receptor (βAR) signaling is susceptible to heterologous desensitization by different neurohormonal stimuli in clinical conditions associated with heart failure. We aim to examine the underlying mechanism of cross talk between βARs and a set of G-protein coupled receptors (GPCRs) activated by hormones/agonists. Methods and results: Rat ventricular cardiomyocytes were used to determine heterologous phosphorylation of βARs under a series of GPCR agonists...
February 21, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28339199/structure-based-discovery-of-new-antagonist-and-biased-agonist-chemotypes-for-the-kappa-opioid-receptor
#3
Zhong Zheng, Xi-Ping Huang, Thomas J Mangano, Rodger Zou, Xin Chen, Saheem Zaidi, Bryan L Roth, Raymond C Stevens, Vsevolod Katritch
The ongoing epidemics of opioid overdose raises an urgent need for effective anti-addiction therapies and addiction-free painkillers. The κ-opioid receptor (KOR) has emerged as a promising target for both indications, raising demand for new chemotypes of KOR antagonists, as well as G-protein-biased agonists. We employed the crystal structure of the KOR-JDTic complex and ligand-optimized structural templates to perform virtual screening of available compound libraries for new KOR ligands. The prospective virtual screening campaign yielded a high 32% hit rate, identifying novel fragment-like and lead-like chemotypes of KOR ligands...
March 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28331048/g-protein-coupled-receptor-kinase-3-and-protein-kinase-c-phosphorylate-the-distal-c-terminal-tail-of-the-chemokine-receptor-cxcr4-and-mediate-recruitment-of-beta-arrestin
#4
Jiansong Luo, John M Busillo, Ralf Stumm, Jeffrey L Benovic
Phosphorylation of G protein-coupled receptors (GPCRs) is a key event for cell signaling and regulation of receptor function. Previously, using tandem mass spectrometry, we identified two phosphorylation sites at the distal C-terminal tail of the chemokine receptor CXCR4, but were unable to determine which specific residues were phosphorylated. Here, we demonstrate that serines 346 and/or 347 (Ser-346/7) of CXCR4 are phosphorylated upon stimulation with the agonist CXCL12 as well as a CXCR4 pepducin, ATI-2341...
March 22, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28328745/gpcr-signaling-via-%C3%AE-arrestin-dependent-mechanisms
#5
Pierre-Yves Jean-Charles, Suneet Kaur, Sudha K Shenoy
β-arrestin1 (or arrestin2) and β-arrestin2 (or arrestin3) are ubiquitously expressed cytosolic adaptor proteins that were originally discovered for their inhibitory role in G protein-coupled receptor (GPCR) signaling via heterotrimeric G proteins. However, further biochemical characterization revealed that β-arrestins do not just 'block' the activated GPCRs, but trigger endocytosis and kinase activation leading to specific signaling pathways that can be localized on endosomes. The signaling pathways initiated by β-arrestins were also found to be independent of G protein activation by GPCRs...
March 17, 2017: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/28325822/structural-basis-for-chemokine-recognition-by-a-g-protein-coupled-receptor-and-implications-for-receptor-activation
#6
Joshua J Ziarek, Andrew B Kleist, Nir London, Barak Raveh, Nicolas Montpas, Julien Bonneterre, Geneviève St-Onge, Crystal J DiCosmo-Ponticello, Chad A Koplinski, Ishan Roy, Bryan Stephens, Sylvia Thelen, Christopher T Veldkamp, Frederick D Coffman, Marion C Cohen, Michael B Dwinell, Marcus Thelen, Francis C Peterson, Nikolaus Heveker, Brian F Volkman
Chemokines orchestrate cell migration for development, immune surveillance, and disease by binding to cell surface heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs). The array of interactions between the nearly 50 chemokines and their 20 GPCR targets generates an extensive signaling network to which promiscuity and biased agonism add further complexity. The receptor CXCR4 recognizes both monomeric and dimeric forms of the chemokine CXCL12, which is a distinct example of ligand bias in the chemokine family...
March 21, 2017: Science Signaling
https://www.readbyqxmd.com/read/28322746/truncation-of-cxcl12-by-cd26-reduces-its-cxc-chemokine-receptor-4-and-atypical-chemokine-receptor-3-dependent-activity-on-endothelial-cells-and-lymphocytes
#7
Rik Janssens, Anneleen Mortier, Daiane Boff, Pieter Ruytinx, Mieke Gouwy, Bo Vantilt, Olav Larsen, Viktorija Daugvilaite, Mette M Rosenkilde, Marc Parmentier, Sam Noppen, Sandra Liekens, Jo Van Damme, Sofie Struyf, Mauro M Teixeira, Flávio A Amaral, Paul Proost
The chemokine CXCL12 or stromal cell-derived factor 1/SDF-1 attracts hematopoietic progenitor cells and mature leukocytes through the G protein-coupled CXC chemokine receptor 4 (CXCR4). In addition, it interacts with atypical chemokine receptor 3 (ACKR3 or CXCR7) and glycosaminoglycans. CXCL12 activity is regulated through posttranslational cleavage by CD26/dipeptidyl peptidase 4 that removes two N-terminal amino acids. CD26-truncated CXCL12 does not induce calcium signaling or chemotaxis of mononuclear cells...
March 16, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28321204/a-comprehensive-view-of-the-%C3%AE-arrestinome
#8
Pascale Crépieux, Anne Poupon, Nathalie Langonné-Gallay, Eric Reiter, Javier Delgado, Martin H Schaefer, Thomas Bourquard, Luis Serrano, Christina Kiel
G protein-coupled receptors (GPCRs) are membrane receptors critically involved in sensing the environment and orchestrating physiological processes. As such, they transduce extracellular signals such as hormone, neurotransmitters, ions, and light into an integrated cell response. The intracellular trafficking, internalization, and signaling ability of ligand-activated GPCRs are controlled by arrestins, adaptor proteins that they interact with upon ligand binding. β-arrestins 1 and 2 in particular are now considered as hub proteins assembling multiprotein complexes to regulate receptor fate and transduce diversified cell responses...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/28319053/alternatively-spliced-mu-opioid-receptor-c-termini-impact-the-diverse-actions-of-morphine
#9
Jin Xu, Zhigang Lu, Ankita Narayan, Valerie P Le Rouzic, Mingming Xu, Amanda Hunkele, Taylor G Brown, William F Hoefer, Grace C Rossi, Richard C Rice, Arlene Martínez-Rivera, Anjali M Rajadhyaksha, Luca Cartegni, Daniel L Bassoni, Gavril W Pasternak, Ying-Xian Pan
Extensive 3' alternative splicing of the mu opioid receptor gene OPRM1 creates multiple C-terminal splice variants. However, their behavioral relevance remains unknown. The present study generated 3 mutant mouse models with truncated C termini in 2 different mouse strains, C57BL/6J (B6) and 129/SvEv (129). One mouse truncated all C termini downstream of Oprm1 exon 3 (mE3M mice), while the other two selectively truncated C-terminal tails encoded by either exon 4 (mE4M mice) or exon 7 (mE7M mice). Studies of these mice revealed divergent roles for the C termini in morphine-induced behaviors, highlighting the importance of C-terminal variants in complex morphine actions...
March 20, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28314853/activation-of-the-orphan-g-protein-coupled-receptor-gpr27-by-surrogate-ligands-promotes-%C3%AE-arrestin-2-recruitment
#10
Nadine Dupuis, Celine Laschet, Delphine Franssen, Martyna Szpakowska, Julie Gilissen, Pierre Geubelle, Arvind Soni, Anne-Simone Parent, Bernard Pirotte, Andy Chevigne, Jean-Claude Twizere, Julien Hanson
G protein-coupled receptors are the most important drug targets for human diseases. An important number of them remain devoid of confirmed ligands. GPR27 is one of these orphan receptors, characterized by a high level of conservation among vertebrates and a predominant expression in the central nervous system. In addition, it has recently been linked to insulin secretion. However, the absence of endogenous or surrogate ligands for GPR27 complicates the examination of its biological function. Our aim was to validate GPR27 signaling pathways and therefore we sought to screen a diversity oriented synthesis library to identify GPR27-specific surrogate agonists...
March 17, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28314120/a-systematic-approach-to-identify-biased-agonists-of-the-apelin-receptor-through-high-throughput-screening
#11
Danielle McAnally, Khandaker Siddiquee, Haleli Sharir, Feng Qi, Sharangdhar Phatak, Jian-Liang Li, Eric Berg, Jordan Fishman, Layton Smith
Biased agonists are defined by their ability to selectively activate distinct signaling pathways of a receptor, and they hold enormous promise for the development of novel drugs that specifically elicit only the desired therapeutic response and avoid potential adverse effects. Unfortunately, most high-throughput screening (HTS) assays are designed to detect signaling of G protein-coupled receptors (GPCRs) downstream of either G protein or β-arrestin-mediated signaling but not both. A comprehensive drug discovery program seeking biased agonists must employ assays that report on the activity of each compound at multiple discrete pathways, particularly for HTS campaigns...
March 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28300398/novel-bivalent-ligands-based-on-the-sumanirole-pharmacophore-reveal-dopamine-d2-receptor-d2r-biased-agonism
#12
Alessandro Bonifazi, Hideaki Yano, Michael P Ellenberger, Ludovic Muller, Vivek Kumar, Mu-Fa Zou, Ning Sheng Cai, Adrian M Guerrero, Amina S Woods, Lei Shi, Amy Hauck Newman
The development of bivalent ligands has attracted interest as a way to potentially improve the selectivity and/or affinity for a specific receptor subtype. The ability to bind two distinct receptor binding sites simultaneously can allow the selective activation of specific G-protein dependent or β-arrestin-mediated cascade pathways. Herein, we developed an extended SAR study using sumanirole (1) as the primary pharmacophore. We found that substitutions in the N-1- and/or N-5-positions, physiochemical properties of those substituents, and secondary aromatic pharmacophores can enhance agonist efficacy for the cAMP inhibition mediated by Gi/o-proteins, while reducing or suppressing potency and efficacy toward β-arrestin recruitment...
March 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28300069/extracellular-%C3%AE-synuclein-induces-sphingosine-1-phosphate-receptor-subtype-1-uncoupled-from-inhibitory-g-protein-leaving-%C3%AE-arrestin-signal-intact
#13
Lifang Zhang, Taro Okada, Shaymaa Mohamed Mohamed Badawy, Chihoko Hirai, Taketoshi Kajimoto, Shun-Ichi Nakamura
Parkinson's disease (PD) is the second most common neurodegenerative disorder. The presence of α-synuclein (α-Syn)-positive intracytoplasmic inclusions, known as Lewy bodies, is the cytopathological hallmark of PD. Increasing bodies of evidence suggest that cell-to-cell transmission of α-Syn plays a role in the progression of PD. Although extracellular α-Syn is known to cause abnormal cell motility, the precise mechanism remains elusive. Here we show that impairment of platelet-derived growth factor-induced cell motility caused by extracellular α-Syn is mainly attributed to selective inhibition of sphingosine 1-phosphate (S1P) signalling...
March 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28298493/deubiquitinating-enzymes-ubp2-and-ubp15-regulate-endocytosis-by-limiting-ubiquitination-and-degradation-of-arts
#14
Hsuan-Chung Ho, Jason A MacGurn, Scott D Emr
Endocytic downregulation of cell-surface proteins is a fundamental cellular process for cell survival and adaptation to environmental stimuli. Ubiquitination of cargo proteins serves as the sorting signal for downstream trafficking, and relies on the Rsp5-ART (arrestin-related trafficking adaptors) ubiquitin ligase adaptor network in yeast. Hence, proper regulation of the abundance and activity of these ligase-adaptor complexes is critical for maintenance of optimal plasma membrane (PM) protein composition...
March 15, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28295363/angiotensin-ii-activates-cav-1-2-ca-2-channels-through-%C3%AE-arrestin2-and-casein-kinase-2-in-mouse-immature-cardiomyocytes
#15
Toshihide Kashihara, Tsutomu Nakada, Katsuhiko Kojima, Toshikazu Takeshita, Mitsuhiko Yamada
Angiotensin II (AngII), the main effector peptide of the renin-angiotensin system, plays important roles in cardiovascular regulation in the perinatal period. Despite the well-known stimulatory effect of AngII on vascular contraction, little is known about regulation of contraction of the immature heart by AngII. Here we found that AngII significantly increased the peak amplitude of twitch Ca(2+) transients by robustly activating L-type CaV 1.2 Ca(2+) (CaV 1.2) channels in mouse immature but not mature cardiomyocytes...
March 15, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28295348/functional-interplay-of-visual-sensitizing-and-screening-pigments-in-the-eyes-of-drosophila-and-other-red-eyed-dipteran-flies
#16
D G Stavenga, M F Wehling, G Belušič
Several fly species have distinctly red-coloured eyes, meaning that the screening pigments that provide a restricted angular sensitivity of the photoreceptors may perform poorly in the longer wavelength range. The functional reasons for the red transparency and possible negative visual effects of the spectral properties of the eye-colouring screening pigments are discussed within the context of the photochemistry, arrestin binding, and turnover of the visual pigments located in the various photoreceptor types...
March 10, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28293165/-pyr-1-apelin-13-1-12-is-a-biologically-active-ace2-metabolite-of-the-endogenous-cardiovascular-peptide-pyr-1-apelin-13
#17
Peiran Yang, Rhoda E Kuc, Aimée L Brame, Alex Dyson, Mervyn Singer, Robert C Glen, Joseph Cheriyan, Ian B Wilkinson, Anthony P Davenport, Janet J Maguire
Aims: Apelin is a predicted substrate for ACE2, a novel therapeutic target. Our aim was to demonstrate the endogenous presence of the putative ACE2 product [Pyr(1)]apelin-13(1-12) in human cardiovascular tissues and to confirm it retains significant biological activity for the apelin receptor in vitro and in vivo. The minimum active apelin fragment was also investigated. Methods and Results: [Pyr(1)]apelin-13 incubated with recombinant human ACE2 resulted in de novo generation of [Pyr(1)]apelin-13(1-12) identified by mass spectrometry...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28291835/adipocyte-arrestin-domain-containing-3-protein-arrdc3-regulates-uncoupling-protein-1-ucp1-expression-in-white-adipose-independently-of-canonical-changes-in-%C3%AE-adrenergic-receptor-signaling
#18
Shannon H Carroll, Ellen Zhang, Bing F Wang, Katherine B LeClair, Arifeen Rahman, David E Cohen, Jorge Plutzky, Parth Patwari, Richard T Lee
Adaptive thermogenesis and cold-induced activation of uncoupling protein 1 (Ucp1) in brown adipose tissue in rodents is well-described and attributed to sympathetic activation of β-adrenergic signaling. The arrestin domain containing protein Arrdc3 is a regulator of obesity in mice and also appears linked to obesity in humans. We generated a mouse with conditional deletion of Arrdc3, and here we present evidence that genetic ablation of Arrdc3 specifically in adipocytes results in increased Ucp1 expression in subcutaneous and parametrial adipose tissue...
2017: PloS One
https://www.readbyqxmd.com/read/28290478/systematic-errors-in-detecting-biased-agonism-analysis-of-current-methods-and-development-of-a-new-model-free-approach
#19
H Ongun Onaran, Caterina Ambrosio, Özlem Uğur, Erzsebet Madaras Koncz, Maria Cristina Grò, Vanessa Vezzi, Sudarshan Rajagopal, Tommaso Costa
Discovering biased agonists requires a method that can reliably distinguish the bias in signalling due to unbalanced activation of diverse transduction proteins from that of differential amplification inherent to the system being studied, which invariably results from the non-linear nature of biological signalling networks and their measurement. We have systematically compared the performance of seven methods of bias diagnostics, all of which are based on the analysis of concentration-response curves of ligands according to classical receptor theory...
March 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28288880/dual-agonist-occupancy-of-orexin-receptor-1-and-cholecystokinin-a-receptor-heterodimers-decreases-g-protein-dependent-signaling-and-migration-in-the-human-colon-cancer-cell-line-ht-29
#20
Bo Bai, Xiaoyu Chen, Rumin Zhang, Xin Wang, Yunlu Jiang, Dandan Li, Zhengwen Wang, Jing Chen
The orexin (OX1R) and cholecystokinin A (CCK1R) receptors play opposing roles in the migration of the human colon cancer cell line HT-29, and may be involved in the pathogenesis and pathophysiology of cancer cell invasion and metastasis. OX1R and CCK1R belong to family A of the G-protein-coupled receptors (GPCRs), but the detailed mechanisms underlying their functions in solid tumor development remain unclear. In this study, we investigated whether these two receptors heterodimerize, and the results revealed novel signal transduction mechanisms...
March 10, 2017: Biochimica et Biophysica Acta
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