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GPCR signaling

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https://www.readbyqxmd.com/read/29777201/novel-smoothened-inhibitors-for-therapeutic-targeting-of-na%C3%A3-ve-and-drug-resistant-hedgehog-pathway-driven-cancers
#1
Qing-Rou Li, Hui Zhao, Xue-Sai Zhang, Henk Lang, Ker Yu
The G protein-coupled receptor (GPCR) smoothened (SMO) is a key signaling component of the sonic hedgehog (Hh) pathway and a clinically validated target for cancer treatment. The FDA-approved SMO inhibitors GDC-0449/Vismodegib and LDE225/Sonidegib demonstrated clinical antitumor efficacy. Nevertheless, relatively high percentage of treated patients would eventually develop acquired cross resistance to both drugs. Here, based on published structure and activity of GDC-0449 inhibitor class, we replaced its amide core with benzimidazole which retained bulk of the SMO-targeting activity as measured in our Hh/SMO/Gli1-reporter system...
May 18, 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29776606/advances-in-membrane-trafficking-and-endosomal-signaling-of-g-protein-coupled-receptors
#2
Aylin C Hanyaloglu
The integration of GPCR signaling with membrane trafficking, as a single orchestrated system, is a theme increasingly evident with the growing reports of GPCR endosomal signaling. Once viewed as a mechanism to regulate cell surface heterotrimeric G protein signaling, the endocytic trafficking system is complex, highly compartmentalized, yet deeply interconnected with cell signaling. The organization of receptors into distinct plasma membrane signalosomes, biochemically distinct endosomal populations, endosomal microdomains, and its communication with distinct subcellular organelles such as the Golgi provides multiple unique signaling platforms that are critical for specifying receptor function physiologically and pathophysiologically...
2018: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/29776605/g-protein-coupled-receptor-resensitization-paradigms
#3
Manveen K Gupta, Maradumane L Mohan, Sathyamangla V Naga Prasad
Cellular responses to extracellular milieu/environment are driven by cell surface receptors that transmit the signal into the cells resulting in a synchronized and measured response. The ability to provide such exquisite responses to changes in external environment is mediated by the tight and yet, deliberate regulation of cell surface receptor function. In this regard, the seven transmembrane G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors that regulate responses like cardiac contractility, vision, and olfaction including platelet activation...
2018: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/29776604/biased-agonism-antagonism-of-cardiovascular-gpcrs-for-heart-failure-therapy
#4
Victoria L Desimine, Katie A McCrink, Barbara M Parker, Shelby L Wertz, Jennifer Maning, Anastasios Lymperopoulos
G protein-coupled receptors (GPCRs) are among the most important drug targets currently used in clinic, including drugs for cardiovascular indications. We now know that, in addition to activating heterotrimeric G protein-dependent signaling pathways, GPCRs can also activate G protein-independent signaling, mainly via the βarrestins. The major role of βarrestin1 and -2, also known as arrestin2 or -3, respectively, is to desensitize GPCRs, i.e., uncoupled them from G proteins, and to subsequently internalize the receptor...
2018: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/29776602/blurring-boundaries-receptor-tyrosine-kinases-as-functional-g-protein-coupled-receptors
#5
Caitrin Crudden, Takashi Shibano, Dawei Song, Naida Suleymanova, Ada Girnita, Leonard Girnita
Receptor tyrosine kinases (RTKs) such as the insulin-like growth factor type 1 receptor (IGF-1R) control important biological activities as well as being involved in pathological processes. Due to their supportive nature in many human cancers they have long been considered attractive therapeutic targets. However, lessons learnt from early targeting trials highlight that a simple "active versus inactive" state model with classical kinase-only signaling is overly simplistic and does not describe reality...
2018: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/29763833/%C3%AE-2-adrenoceptor-signalling-bias-in-asthma-and-copd-and-the-potential-impact-on-the-comorbidities-associated-with-these-diseases
#6
REVIEW
Maria Gabriella Matera, Clive Page, Barbara Rinaldi
Inhaled selective β2-agonists are the most widely used treatment for obstructive airway diseases. The classical mechanism of action of these drugs is considered as their ability to activate β2-adrenergic receptors (β2-AR) on airway smooth muscle leading to G-protein activation and subsequent generation of c-AMP causing bronchodilation. However, there is now growing evidence to suggest that binding of β2-agonists to β2-AR is pleotropically coupled to many intracellular pathways whereby depending on the state of the β2-AR when activated, a subset of different intracellular responses can be triggered...
May 12, 2018: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29752624/g%C3%AE-%C3%AE-snare-interactions-and-their-behavioral-effects
#7
Simon Alford, Heidi Hamm, Shelagh Rodriguez, Zack Zurawski
Presynaptic terminals possess interlocking molecular mechanisms that control exocytosis. An example of such complexity is the modulation of release by presynaptic G Protein Coupled Receptors (GPCRs). GPCR ubiquity at synapses-GPCRs are present at every studied presynaptic terminal-underlies their critical importance in synaptic function. GPCRs mediate presynaptic modulation by mechanisms including via classical Gα effectors, but membrane-delimited actions of Gβγ can also alter probability of release by altering presynaptic ionic conductances...
May 11, 2018: Neurochemical Research
https://www.readbyqxmd.com/read/29752421/making-useful-gadgets-with-miniaturized-g-proteins
#8
Kirill A Martemyanov, Mikel Garcia-Marcos
G protein-coupled receptors (GPCRs) relay information from extracellular stimuli to intracellular responses in a wide range of physiological and pathological processes, but understanding their complex effects in live cells is a daunting task. In this issue of JBC, Wan et al repurpose "mini G proteins"-previously used as affinity tools for structural studies-to develop a suite of probes to visualize GPCR activation in live cells. The approach is expected to revolutionize our understanding of the spatiotemporal control and mechanisms of GPCR signaling...
May 11, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29749524/multifaceted-regulation-and-functions-of-yap-taz-in-tumors-review
#9
Huirong Liu, Suya Du, Tiantian Lei, Hailian Wang, Xia He, Rongsheng Tong, Yi Wang
The Hippo pathway, initially identified through screenings for mutant tumor suppressors in Drosophila, is an evolutionarily conserved signaling pathway that controls organ size by regulating cell proliferation and apoptosis. Abnormal regulation of the Hippo pathway may lead to cancer in mammals. As the major downstream effectors of the Hippo pathway, unphosphorylated Yes-associated protein (YAP) and its homolog transcriptional co-activator TAZ (also called WWTR1) (hereafter called YAP/TAZ) are translocated into the nucleus...
May 8, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29743977/formyl-peptide-receptor-1-modulates-endothelial-cell-functions-by-nadph-oxidase-dependent-vegfr2-transactivation
#10
Fabio Cattaneo, Martina Castaldo, Melania Parisi, Raffaella Faraonio, Gabriella Esposito, Rosario Ammendola
In the vasculature, NADPH oxidase is the main contributor of reactive oxygen species (ROS) which play a key role in endothelial signalling and functions. We demonstrate that ECV304 cells express p47phox , p67phox , and p22phox subunits of NADPH oxidase, as well as formyl peptide receptors 1 and 3 (FPR1/3), which are members of the GPCR family. By RT-PCR, we also detected Flt-1 and Flk-1/KDR in these cells. Stimulation of FPR1 by N-fMLP induces p47phox phosphorylation, which is the crucial event for NADPH oxidase-dependent superoxide production...
2018: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/29739625/gpcrs-and-signal-transducers-interaction-stoichiometry
#11
REVIEW
Vsevolod V Gurevich, Eugenia V Gurevich
Until the late 1990s, class A G protein-coupled receptors (GPCRs) were believed to function as monomers. Indirect evidence that they might internalize or even signal as dimers has emerged, along with proof that class C GPCRs are obligatory dimers. Crystal structures of GPCRs and their much larger binding partners were consistent with the idea that two receptors might engage a single G protein, GRK, or arrestin. However, recent biophysical, biochemical, and structural evidence invariably suggests that a single GPCR binds G proteins, GRKs, and arrestins...
May 5, 2018: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/29735399/emerging-paradigm-of-intracellular-targeting-of-g-protein-coupled-receptors
#12
REVIEW
Madhu Chaturvedi, Justin Schilling, Alexandre Beautrait, Michel Bouvier, Jeffrey L Benovic, Arun K Shukla
G protein-coupled receptors (GPCRs) recognize a diverse array of extracellular stimuli, and they mediate a broad repertoire of signaling events involved in human physiology. Although the major effort on targeting GPCRs has typically been focused on their extracellular surface, a series of recent developments now unfold the possibility of targeting them from the intracellular side as well. Allosteric modulators binding to the cytoplasmic surface of GPCRs have now been described, and their structural mechanisms are elucidated by high-resolution crystal structures...
May 4, 2018: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/29734668/emerging-roles-of-g-protein-coupled-receptors-in-hepatocellular-carcinoma
#13
REVIEW
Wen-Ting Peng, Wu-Yi Sun, Xin-Ran Li, Jia-Chang Sun, Jia-Jia Du, Wei Wei
Among a great variety of cell surface receptors, the largest superfamily is G protein-coupled receptors (GPCRs), also known as seven-transmembrane domain receptors. GPCRs can modulate diverse signal-transduction pathways through G protein-dependent or independent pathways which involve β-arrestins, G protein receptor kinases (GRKs), ion channels, or Src kinases under physiological and pathological conditions. Recent studies have revealed the crucial role of GPCRs in the tumorigenesis and the development of cancer metastasis...
May 4, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29733762/filling-gaps-in-g-protein-coupled-receptor-gpcr-mediated-ras-adaptation-and-chemotaxis
#14
Xu Xuehua
Eukaryotic cells sense and migrate toward chemoattractant gradients using G protein-coupled receptor (GPCR) signaling pathways. The fascinating feature of chemotaxis is that cells migrate through chemoattractant gradients with huge concentration ranges by "adaptation." Adaptive cells no longer respond to the present stimulus but remain sensitive to stronger stimuli, providing the fundamental strategy for chemotaxis through gradients with a broad range of concentrations. Ras activation is the first step in the GPCR-mediated chemosensing signaling pathways that displays adaptation...
May 7, 2018: Small GTPases
https://www.readbyqxmd.com/read/29733063/adrenergic-signaling-molecular-complexes
#15
Rocío Alcántara-Hernández, Aurelio Hernández-Méndez
Adrenaline and noradrenaline bind to membrane receptors of the superfamily of G protein-coupled receptors (GPCR) in target cells, where they modulate physiological responses such as metabolism, vasoconstriction, vasodilation and proliferation. Alteration in their function is associated with conditions such as hypertension, benign prostatic hyperplasia and cardiac hypertrophy. In response to adrenaline, receptors form signaling complexes, which enables adrenergic action to be specific, rapid and efficient. These signaling complexes or signalosomes are composed of kinases, phosphatases, and adapter and scaffold proteins, which together modulate the receptor function...
2018: Gaceta Médica de México
https://www.readbyqxmd.com/read/29731302/quantitative-control-of-gpcr-organization-and-signaling-by-endocytosis-in-epithelial-morphogenesis
#16
Ankita Jha, Thomas S van Zanten, Jean-Marc Philippe, Satyajit Mayor, Thomas Lecuit
Tissue morphogenesis arises from controlled cell deformations in response to cellular contractility. During Drosophila gastrulation, apical activation of the actomyosin networks drives apical constriction in the invaginating mesoderm and cell-cell intercalation in the extending ectoderm. Myosin II (MyoII) is activated by cell-surface G protein-coupled receptors (GPCRs), such as Smog and Mist, that activate G proteins, the small GTPase Rho1, and the kinase Rok. Quantitative control over GPCR and Rho1 activation underlies differences in deformation of mesoderm and ectoderm cells...
April 25, 2018: Current Biology: CB
https://www.readbyqxmd.com/read/29730398/capa-periviscerokinin-mediated-activation-of-mapk-erk-signaling-through-gq-plc-pkc-dependent-cascade-and-reciprocal-erk-activation-dependent-internalized-kinetics-of-bom-capa-pvk-receptor-2
#17
Zhangfei Shen, Xiaoyuan Yang, Yu Chen, Liangen Shi
Bombyx mori neuropeptide G protein-coupled receptor (BNGR)-A27 is a specific receptor for B. mori capability (CAPA) periviscerokinin (PVK), that is, Bom-CAPA-PVK receptor 2. Upon stimulation of Bom-CAPA-PVK-1 or -PVK-2, Bom-CAPA-PVK receptor 2 significantly increases cAMP-response element-controlled luciferase activity and Ca2+ mobilization in a Gq inhibitor-sensitive manner. However, the underlying mechanism(s) for CAPA/CAPA receptor system mediation of extracellular signal-regulated kinases1/2 (ERK1/2) activation remains to be explained further...
May 3, 2018: Insect Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/29727618/s-nitrosylation-of-%C3%AE-arrestins-biases-receptor-signaling-and-confers-ligand-independence
#18
Hiroki Hayashi, Douglas T Hess, Rongli Zhang, Keiki Sugi, Huiyun Gao, Bea L Tan, Dawn E Bowles, Carmelo A Milano, Mukesh K Jain, Walter J Koch, Jonathan S Stamler
Most G protein-coupled receptors (GPCRs) signal through both heterotrimeric G proteins and β-arrestins (βarr1 and βarr2). Although synthetic ligands can elicit biased signaling by G protein- vis-à-vis βarr-mediated transduction, endogenous mechanisms for biasing signaling remain elusive. Here we report that S-nitrosylation of a novel site within βarr1/2 provides a general mechanism to bias ligand-induced signaling through GPCRs by selectively inhibiting βarr-mediated transduction. Concomitantly, S-nitrosylation endows cytosolic βarrs with receptor-independent function...
May 3, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29723131/insulin-acts-as-a-repressive-factor-to-inhibit-the-ability-of-par2-to-induce-islet-cell-transdifferentiation
#19
Seung-Hee Lee, Ergeng Hao, David Scharp, Fred Levine
Recently, we showed that pancreatitis in the context of profound β-cell deficiency was sufficient to induce islet cell transdifferentiation. In some circumstances, this effect was sufficient to result in recovery from severe diabetes. More recently, we showed that the molecular mechanism by which pancreatitis induced β-cell neogenesis by transdifferentiation was activation of an atypical GPCR called Protease-Activated Receptor 2 (PAR2). However, the ability of PAR2 to induce transdifferentiation occurred only in the setting of profound β-cell deficiency, implying the existence of a repressive factor from those cells...
May 3, 2018: Islets
https://www.readbyqxmd.com/read/29720660/catalytic-activation-of-%C3%AE-arrestin-by-gpcrs
#20
Kelsie Eichel, Damien Jullié, Benjamin Barsi-Rhyne, Naomi R Latorraca, Matthieu Masureel, Jean-Baptiste Sibarita, Ron O Dror, Mark von Zastrow
β-arrestins are critical regulator and transducer proteins for G-protein-coupled receptors (GPCRs). β-arrestin is widely believed to be activated by forming a stable and stoichiometric GPCR-β-arrestin scaffold complex, which requires and is driven by the phosphorylated tail of the GPCR. Here we demonstrate a distinct and additional mechanism of β-arrestin activation that does not require stable GPCR-β-arrestin scaffolding or the GPCR tail. Instead, it occurs through transient engagement of the GPCR core, which destabilizes a conserved inter-domain charge network in β-arrestin...
May 2, 2018: Nature
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