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Regine Brox, Lampros Milanos, Noureldin Saleh, Paul Baumeister, Armin Buschauer, Dagmar Hofmann, Markus R Heinrich, Timothy Clark, Nuska Tschammer
Our recent explorations of allosteric modulators (AMs) with improved properties resulted in the identification of two biased negative AMs, N-1-{[3-(4-Ethoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimi-din2yl]ethyl}-4-(4-fluorobutoxy)-N-[(1-methylpiperidin-4-yl)me-thyl}]butanamide (BD103) and {5-[(N-{1-[3-(4-ethoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl]ethyl-2-[4-fluoro-3-(trifluoromethyl)phenyl]acetamido)methyl]-2-fluorophenyl}boronic acid (BD064), that exhibited probe-dependent inhibition of the chemokine receptor CXCR3 signaling...
January 17, 2018: Molecular Pharmacology
Yutaro Shiraishi, Mei Natsume, Yutaka Kofuku, Shunsuke Imai, Kunio Nakata, Toshimi Mizukoshi, Takumi Ueda, Hideo Iwaï, Ichio Shimada
The C-terminal region of G-protein-coupled receptors (GPCRs), stimulated by agonist binding, is phosphorylated by GPCR kinases, and the phosphorylated GPCRs bind to arrestin, leading to the cellular responses. To understand the mechanism underlying the formation of the phosphorylated GPCR-arrestin complex, we performed NMR analyses of the phosphorylated β2-adrenoceptor (β2AR) and the phosphorylated β2AR-β-arrestin 1 complex, in the lipid bilayers of nanodisc. Here we show that the phosphorylated C-terminal region adheres to either the intracellular side of the transmembrane region or lipids, and that the phosphorylation of the C-terminal region allosterically alters the conformation around M2155...
January 15, 2018: Nature Communications
Osamu Takenouchi, Hideaki Yoshimura, Takeaki Ozawa
Intracellular trafficking of G protein-coupled receptors (GPCRs) controls their localization and degradation, which affects a cell's ability to adapt to extracellular stimuli. Although the perturbation of trafficking induces important diseases, these trafficking mechanisms are poorly understood. Herein, we demonstrate an optogenetic method using an optical dimerizer, cryptochrome (CRY) and its partner protein (CIB), to analyze the trafficking mechanisms of GPCRs and their regulatory proteins. Temporally controlling the interaction between β-arrestin and β2-adrenergic receptor (ADRB2) reveals that the duration of the β-arrestin-ADRB2 interaction determines the trafficking pathway of ADRB2...
January 12, 2018: Scientific Reports
Laura Patrussi, Nagaja Capitani, Francesca Cattaneo, Noemi Manganaro, Alessandra Gamberucci, Federica Frezzato, Veronica Martini, Andrea Visentin, Pier Giuseppe Pelicci, Mario M D'Elios, Livio Trentin, Gianpietro Semenzato, Cosima T Baldari
Neoplastic cell traffic abnormalities are central to the pathogenesis of chronic lymphocytic leukemia (CLL). Enhanced CXC chemokine receptor-4 (CXCR4) and chemokine receptor-7 (CCR7) recycling contributes to the elevated surface levels of these receptors on CLL cells. Here we have addressed the role of p66Shc, a member of the Shc family of protein adaptors the expression of which is defective in CLL cells, in CXCR4/CCR7 recycling. p66Shc reconstitution in CLL cells reduced CXCR4/CCR7 recycling, lowering their surface levels and attenuating B-cell chemotaxis, due to their accumulation in Rab5+ endosomes as serine-phosphoproteins bound to β-arrestin...
January 12, 2018: Oncogene
Daniel Hilger, Matthieu Masureel, Brian K Kobilka
G-protein-coupled receptors (GPCRs) relay numerous extracellular signals by triggering intracellular signaling through coupling with G proteins and arrestins. Recent breakthroughs in the structural determination of GPCRs and GPCR-transducer complexes represent important steps toward deciphering GPCR signal transduction at a molecular level. A full understanding of the molecular basis of GPCR-mediated signaling requires elucidation of the dynamics of receptors and their transducer complexes as well as their energy landscapes and conformational transition rates...
January 2018: Nature Structural & Molecular Biology
Trevor D Lamb, Hardip R Patel, Aaron Chuah, David M Hunt
Different isoforms of the genes involved in phototransduction are expressed in vertebrate rod and cone photoreceptors, providing a unique example of parallel evolution via gene duplication. In this study, we determine the molecular phylogeny of the proteins underlying the shut-off steps of phototransduction in the agnathan and jawed vertebrate lineages. For the G-protein receptor kinases (GRKs), the GRK1 and GRK7 divisions arose prior to the divergence of tunicates, with further expansion during the two rounds of whole-genome duplication (2R); subsequently, jawed and agnathan vertebrates retained different subsets of three isoforms of GRK...
January 2018: Open Biology
Bing Huang, Youxing Li, Deqin Cheng, Guanhong He, Xing Liu, Lan Ma
Extinction learning of cocaine-associated contextual cues can help prevent cocaine addicts from relapsing. Pharmacological manipulation of β-adrenergic receptor (β-AR) during extinction learning is being developed as a potential strategy to treat drug addiction. We demonstrated that the extinction learning of cocaine-associated memory was mediated by β-arrestin2-biased but not heterotrimeric guanine nucleotide-binding protein (G protein)-dependent β-adrenergic signaling. We found that administration of the nonbiased β-AR antagonist propranolol, but not the G protein-biased β-AR antagonist carvedilol, blocked extinction learning of cocaine-conditioned place preference and the associated ERK activation in the infralimbic prefrontal cortex...
January 9, 2018: Science Signaling
Sergey A Vishnivetskiy, Lori S Sullivan, Sara J Bowne, Stephen P Daiger, Eugenia V Gurevich, Vsevolod V Gurevich
Purpose: The purpose of this study was to identify the molecular defect in the disease-causing human arrestin-1 C147F mutant. Methods: The binding of wild-type (WT) human arrestin-1 and several mutants with substitutions in position 147 (including C147F, which causes dominant retinitis pigmentosa in humans) to phosphorylated and unphosphorylated light-activated rhodopsin was determined. Thermal stability of WT and mutant human arrestin-1, as well as unfolded protein response in 661W cells, were also evaluated...
January 1, 2018: Investigative Ophthalmology & Visual Science
Jeffrey S Smith, Robert J Lefkowitz, Sudarshan Rajagopal
G protein-coupled receptors (GPCRs) are the largest class of receptors in the human genome and some of the most common drug targets. It is now well established that GPCRs can signal through multiple transducers, including heterotrimeric G proteins, GPCR kinases and β-arrestins. While these signalling pathways can be activated or blocked by 'balanced' agonists or antagonists, they can also be selectively activated in a 'biased' response. Biased responses can be induced by biased ligands, biased receptors or system bias, any of which can result in preferential signalling through G proteins or β-arrestins...
January 5, 2018: Nature Reviews. Drug Discovery
Assunta Venuti, Claudia Pastori, Gabriel Siracusano, Rosamaria Pennisi, Agostino Riva, Massimo Tommasino, Maria Teresa Sciortino, Lucia Lopalco
The exposure to CCR5 (CC chemokine receptor 5) specific natural antibodies in vitro produces a Class B β-arrestin2-dependent CCR5 retention with the aid of ERK1, due to the formation of a CCR5 signalosome, which remains stable for at least 48 h. Considering that β-arrestins and MAPKs are receptive to environmental signals, their signal complexes could be one of the key junction for GPCRs internalization related signal transduction. Here, we demonstrate that, in T cells, the phosphorylation status of either CCR5 receptor or ERK1 protein is necessary to drive the internalized receptor into the early endosomes, forming the CCR5 signalosome...
December 28, 2017: Viruses
Isaac J Dripps, Brett T Boyer, Richard R Neubig, Kenner C Rice, John R Traynor, Emily M Jutkiewicz
BACKGROUND AND PURPOSE: G protein-coupled receptors exist in multiple conformations that can engage distinct signaling mechanisms which in turn may lead to diverse behavioral outputs. In rodent models, activation of the delta opioid receptor (δ-receptor) has been shown to elicit antihyperalgesia, antidepressant-like effects, and convulsions. We recently showed that these δ-receptor-mediated behaviors are differentially regulated by the GTPase-activating protein regulator of G protein signaling 4 (RGS4), which facilitates termination of G protein signaling...
December 26, 2017: British Journal of Pharmacology
Hung-Chih Chang, Po-Han Huang, Fu-Sheng Syu, Chia-Hung Hsieh, Sunny Li-Yun Chang, Jean Lu, Hui-Chen Chen
Trafficking and recruitment of immune cells to the site of inflammation with spatial and temporal synchronization is crucial for the development of allergic airway inflammation. Particularly, chemokines are known to be key players in these processes. Previous studies revealed that the CXCL12/CXCR4 axis plays an important role in regulating allergic airway inflammation. However, the role of CXCR7, a recently discovered second receptor for CXCL12, in regulating airway inflammation has not been explored. Initially, CXCR7 was considered as a decoy receptor; however, numerous subsequent studies revealed that engagement of CXCR7 triggered its own signaling or modulated CXCR4-mediated signaling...
December 18, 2017: Immunology
Ashley N Guillory, Robert P Clayton, Anesh Prasai, Amina El Ayadi, David N Herndon, Celeste C Finnerty
Burn injury detrimentally affects the myocardium, primarily due to over-activation of β-adrenergic receptors (β-AR). Autopsy reports from our institution reveal that patients often suffer from right ventricle (RV) failure. Since burn injury affects β-AR signaling in the left ventricle (LV), we proposed that β-AR signaling may also be altered in the RV. A rodent model with a scald burn of 60% of the total body surface area was used to test this hypothesis. Ventricles were isolated 7 days post-burn. We examined the expression of β-ARs via Western blotting and the mRNA expression of downstream signaling proteins via qRT-PCR...
2017: PloS One
Jialu Wang, Kenji Hanada, Clarice Gareri, Howard A Rockman
Ligand activation of the angiotensin II type 1 receptor (AT1R), a member of the G protein-coupled receptor (GPCR) family, stimulates intracellular signaling to mediate a variety of physiological responses. The AT1R is also known to be a mechanical sensor. When activated by mechanical stretch, the AT1R can signal via the multifunctional adaptor protein β-arrestin, rather than through classical heterotrimeric G protein pathways. To date, the AT1R conformation induced by membrane stretch in the absence of ligand was thought to be the same as that induced by β-arrestin-biased agonists, which selectively engage β-arrestin thereby preventing G protein coupling...
December 12, 2017: Journal of Cellular Biochemistry
John D McCorvy, Kyle V Butler, Brendan Kelly, Katie Rechsteiner, Joel Karpiak, Robin M Betz, Bethany L Kormos, Brian K Shoichet, Ron O Dror, Jian Jin, Bryan L Roth
Development of biased ligands targeting G protein-coupled receptors (GPCRs) is a promising approach for current drug discovery. Although structure-based drug design of biased agonists remains challenging even with an abundance of GPCR crystal structures, we present an approach for translating GPCR structural data into β-arrestin-biased ligands for aminergic GPCRs. We identified specific amino acid-ligand contacts at transmembrane helix 5 (TM5) and extracellular loop 2 (EL2) responsible for Gi/o and β-arrestin signaling, respectively, and targeted those residues to develop biased ligands...
December 11, 2017: Nature Chemical Biology
Yun Shi, Zhen-Ju Shu, Hanzhou Wang, Jeffrey L Barnes, Chih-Ko Yeh, Paramita M Ghosh, Michael S Katz, Amrita Kamat
Increased β-adrenergic receptor (β-AR)-mediated activation of adenylyl cyclase (AC) in rat liver during aging has been linked to age-related increases in hepatic glucose output and hepatosteatosis. In this study we investigated the expression of β-ARs, individual receptor subtypes, and G protein-coupled receptor (GPCR) regulatory proteins in livers from aging rats. Radioligand binding studies demonstrated that β-AR density increased by >3-fold in hepatocyte membranes from senescent (24 mo old) compared to young adult (7 mo old) rats, and that this phenomenon was blocked by food restriction which is known to retard aging processes in rodents...
December 6, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Dali Wang, Hua Yu, Xiangdong Liu, Jianqiang Liu, Chen Song
G protein-coupled receptors (GPCRs) constitute a large family of membrane proteins that plays a key role in transmembrane signal transduction and draw wide attention since it was discovered. Arrestin is a small family of proteins which can bind to GPCRs, block G protein interactions and redirect signaling to G-protein-independent pathways. The detailed mechanism of how arrestin interacts with GPCR remains elusive. Here, we conducted molecular dynamics simulations with coarse-grained (CG) and all-atom (AA) models to study the complex structure formed by arrestin and rhodopsin, a prototypical GPCR, in a POPC bilayer...
December 5, 2017: Scientific Reports
Qing Song, Qing Ji, Qi Li
β‑arrestins are a family of adaptor proteins that regulate the signaling and trafficking of various G protein‑coupled receptors (GPCRs). They consist of β‑arrestin1 and β‑arrestin2 and are considered to be scaffolding proteins. β‑arrestins regulate cell proliferation, promote cell invasion and migration, transmit anti‑apoptotic survival signals and affect other characteristics of tumors, including tumor growth rate, angiogenesis, drug resistance, invasion and metastatic potential. It has been demonstrated that β‑arrestins serve roles in various physiological and pathological processes and exhibit a similar function to GPCRs...
November 27, 2017: International Journal of Molecular Medicine
Linda Sundström, Susanna Myhre, Monika Sundqvist, Andrea Ahnmark, William McCoull, Piotr Raubo, Sam D Groombridge, Magnus Polla, Ann-Christin Nyström, Lisbeth Kristensson, Mats Någård, Maria Sörhede Winzell
The mechanism behind the glucose lowering effect occurring after specific activation of GPR120 is not completely understood. In this study, a potent and selective GPR120 agonist was developed and its pharmacological properties were compared with the previously described GPR120 agonist Metabolex-36. Effects of both compounds on signaling pathways and GLP-1 secretion were investigated in vitro. The acute glucose lowering effect was studied in lean wild-type and GPR120 null mice following oral or intravenous glucose tolerance tests...
2017: PloS One
Baosheng Ge, Jun Lao, Jiqiang Li, Yao Chen, Yanzhuo Song, Fang Huang
Dimerization and oligomerization of G-protein coupled receptors (GPCRs) have emerged as important characters during their trans-membrane signal transduction. However, until now the relationship between GPCR dimerization and their trans-membrane signal transduction function is still uncovered. Here, using pertussis toxin (PTX) to decouple the receptor from G protein complex and with single-molecule imaging, we show that in the presence of agonist, cells treated with PTX showed a decrease in the number of dimers and oligomers on the cell surface compared with untreated ones, which suggests that oligomeric status of CXCR4 could be significantly influenced by the decoupling of G protein complex during its signal transduction process...
December 4, 2017: Scientific Reports
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