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https://www.readbyqxmd.com/read/29776952/activity-based-concept-to-screen-biological-matrices-for-opiates-and-synthetic-opioids
#1
Annelies Cannaert, Lakshmi Vasudevan, Melissa Friscia, Amanda L A Mohr, Sarah M R Wille, Christophe P Stove
BACKGROUND: Detection of new highly potent synthetic opioids is challenging as new compounds enter the market. Here we present a novel screening method for the detection of opiates and (synthetic) opioids based on their activity. METHODS: A cell-based system was set up in which activation of the μ -opioid receptor (MOR) led to recruitment of β-arrestin 2, resulting in functional complementation of a split NanoLuc luciferase and allowing readout via bioluminescence...
May 18, 2018: Clinical Chemistry
https://www.readbyqxmd.com/read/29776605/g-protein-coupled-receptor-resensitization-paradigms
#2
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/29776602/blurring-boundaries-receptor-tyrosine-kinases-as-functional-g-protein-coupled-receptors
#3
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/29775410/apelin-and-apj-orchestrate-complex-tissue-specific-control-of-cardiomyocyte-hypertrophy-and-contractility-in-the-hypertrophy-heart-failure-transition
#4
Victoria Nicole Parikh, Jing Liu, Ching Shang, Christopher Woods, Alex Chia Yu Chang, Mingming Zhao, David N Charo, Zachary Grunwald, Yong Huang, Kinya Seo, Philip S Tsao, Daniel Bernstein, Pilar Ruiz-Lozano, Thomas Quertermous, Euan A Ashley
The G protein coupled receptor APJ is a promising therapeutic target for heart failure. Constitutive deletion of APJ in the mouse is protective against the hypertrophy-heart failure transition via elimination of ligand-independent, β-arrestin dependent stretch transduction. However, the cellular origin of this stretch transduction and the details of its interaction with apelin signaling remain unknown. We generated mice with conditional elimination of APJ in the endothelium (APJendo-/- ) and myocardium (APJmyo-/- )...
May 18, 2018: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/29766401/penehyclidine-hydrochloride-decreases-pulmonary-microvascular-endothelial-inflammatory-injury-through-a-beta-arrestin-1-dependent-mechanism
#5
Fei Zheng, Fei Xiao, Qing-Hong Yuan, Qiang-Sheng Liu, Zong-Ze Zhang, Yan-Lin Wang, Jia Zhan
Penehyclidine hydrochloride (PHC), a type of hyoscyamus drug, has both antimuscarinic and antinicotinic activities and retains potent central and peripheral anticholinergic activities. Compared with other hyoscyamine, the notable advantage of PHC is that it has few M2 receptor-associated cardiovascular side effects. Recent studies and clinical trials have suggested that treatment with penehyclidine hydrochloride may also possess good effects in the treatment of lung injury. The mechanism responsible for this effect has yet to be determined; however, one possibility is that they might do so by a direct effect on pulmonary vascular endothelium...
May 15, 2018: Inflammation
https://www.readbyqxmd.com/read/29765373/compartmentalized-cyclic-amp-production-by-the-bordetella-pertussis-and-bacillus-anthracis-adenylate-cyclase-toxins-differentially-affects-the-immune-synapse-in-t-lymphocytes
#6
Vijay B Arumugham, Cristina Ulivieri, Anna Onnis, Francesca Finetti, Fiorella Tonello, Daniel Ladant, Cosima T Baldari
A central feature of the immune synapse (IS) is the tight compartmentalization of membrane receptors and signaling mediators that is functional for its ability to coordinate T cell activation. Second messengers centrally implicated in this process, such as Ca2+ and diacyl glycerol, also undergo compartmentalization at the IS. Current evidence suggests a more complex scenario for cyclic AMP (cAMP), which acts both as positive and as negative regulator of T-cell antigen receptor (TCR) signaling and which, as such, must be subjected to a tight spatiotemporal control to allow for signaling at the IS...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29752864/%C3%AE-blockers-interfere-with-cell-homing-receptors-and-regulatory-proteins-in-a-model-of-spontaneously-hypertensive-rats
#7
Bruna Eibel, Melissa Kristochek, Thiago R Peres, Lucinara D Dias, Daniela R Dartora, Karina R Casali, Renato A K Kalil, Alexandre M Lehnen, Maria Claudia Irigoyen, Melissa M Markoski
AIM: To examine the interference of β-blockers with the chemokine stromal cell-derived factor-1 (SDF-1) found in cell homing receptors, C-X-C chemokine receptor type 4 (CXCR-4) and CXCR-7 and regulatory proteins of homing pathways, we administered atenolol, carvedilol, metoprolol and propranolol for 30 days using an orogastric tube to hypertensive rats. METHOD: We collected blood samples before and after treatment and quantified the levels of SDF-1 with enzyme linked immunosorbent assay (ELISA)...
May 12, 2018: Cardiovascular Therapeutics
https://www.readbyqxmd.com/read/29739625/gpcrs-and-signal-transducers-interaction-stoichiometry
#8
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
#9
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
#10
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/29734363/%C3%AE-arrestin1-and-2-differentially-regulate-pacap-induced-pac1-receptor-signaling-and-trafficking
#11
Yusuke Shintani, Atsuko Hayata-Takano, Keita Moriguchi, Takanobu Nakazawa, Yukio Ago, Atsushi Kasai, Kaoru Seiriki, Norihito Shintani, Hitoshi Hashimoto
A pituitary adenylate cyclase-activating polypeptide (PACAP)-specific receptor, PAC1R, is coupled with multiple signal transduction pathways including stimulation of adenylate cyclase, phospholipase C and extracellular-signal regulated kinase (ERK)1/2. PAC1R has been shown to exert its long-lasting and potent signals via β-arrestin1 and β-arrestin2. However, the precise roles of the two β-arrestin isoforms in PACAP-PAC1R signaling remain unclear. Here we examined the interaction between the two β-arrestin isoforms and PAC1R, β-arrestin-dependent PAC1R subcellular localization and ERK1/2 activation...
2018: PloS One
https://www.readbyqxmd.com/read/29733100/does-nalbuphine-have-a-niche-in-managing-pain
#12
Mellar P Davis, Carlos Fernandez, Sally Regel, Mary Lynn McPherson
Nalbuphine has been commercially available for 40 years for the treatment of acute pain; few studies have centered on management of chronic pain. Nalbuphine unique pharmacology is an advantage in pain management. It is µ antagonist, partial κ agonist for G-proteins and beta-arrestin-2. Benefits are related to G-protein interactions resulting in less nausea, pruritus, and respiratory depression than morphine. At low doses, nalbuphine reduces side effects particularly respiratory depression without loss of analgesia when combined with potent opioids...
March 2018: Journal of Opioid Management
https://www.readbyqxmd.com/read/29731302/quantitative-control-of-gpcr-organization-and-signaling-by-endocytosis-in-epithelial-morphogenesis
#13
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/29727618/s-nitrosylation-of-%C3%AE-arrestins-biases-receptor-signaling-and-confers-ligand-independence
#14
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/29722902/tolerance-to-high-internalizing-delta-opioid-receptor-agonist-is-critically-mediated-by-arrestin-2
#15
Ana Vicente-Sanchez, Isaac J Dripps, Alycia F Tipton, Heba Akbari, Areeb Akbari, Emily M Jutkiewicz, Amynah A Pradhan
BACKGROUND AND PURPOSE: Delta opioid receptor (δOR) agonists are potent antihyperalgesics in chronic pain models, but tolerance develops after prolonged use. Previous evidence indicates that distinct forms of tolerance occur depending on the internalization properties of δOR agonists. Due to the importance of arrestins in receptor internalization, we investigated the role of arrestin 2 (β-arrestin 1) in mediating the development of tolerance induced by high- and low-internalizing δOR agonists...
May 3, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29721954/identifying-key-networks-linked-to-light-independent-photoreceptor-degeneration-in-visual-arrestin-1-knockout-mice
#16
Hwa Sun Kim, Shun-Ping Huang, Eun-Jin Lee, Cheryl Mae Craft
When visual arrestin 1 (ARR1, S-antigen, 48 KDa protein) was genetically knocked out in mice (original Arr1 -/- , designated Arr1 -/-A ), rod photoreceptors degenerated in a light-dependent manner. Subsequently, a light-independent cone dystrophy was identified with minimal rod death in ARR1 knockout mice (Arr1 -/-A Arr4 +/+ , designated Arr1 -/-B ), which were F2 littermates from breeding the original Arr1 -/-A and cone arrestin knockout 4 (Arr4 -/- ) mice. To resolve the genetic and phenotypic differences between the two ARR1 knockouts, we performed Affymetrix™ exon array analysis to focus on the potential differential gene expression profile and to explore the molecular and cellular pathways leading to this observed susceptibility to cone dystrophy in Arr1 -/-B compared to Arr1 -/-A or control Arr1 +/+ Arr4 +/+ (wild type [WT])...
2018: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29720660/catalytic-activation-of-%C3%AE-arrestin-by-gpcrs
#17
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
https://www.readbyqxmd.com/read/29720655/molecular-mechanism-of-gpcr-mediated-arrestin-activation
#18
Naomi R Latorraca, Jason K Wang, Brian Bauer, Raphael J L Townshend, Scott A Hollingsworth, Julia E Olivieri, H Eric Xu, Martha E Sommer, Ron O Dror
Despite intense interest in discovering drugs that cause G-protein-coupled receptors (GPCRs) to selectively stimulate or block arrestin signalling, the structural mechanism of receptor-mediated arrestin activation remains unclear1,2 . Here we reveal this mechanism through extensive atomic-level simulations of arrestin. We find that the receptor's transmembrane core and cytoplasmic tail-which bind distinct surfaces on arrestin-can each independently stimulate arrestin activation. We confirm this unanticipated role of the receptor core, and the allosteric coupling between these distant surfaces of arrestin, using site-directed fluorescence spectroscopy...
May 2, 2018: Nature
https://www.readbyqxmd.com/read/29713080/complex-formation-between-the-vasopressin-1b-receptor-%C3%AE-arrestin-2-and-the-%C3%AE-opioid-receptor-underlies-morphine-tolerance
#19
Taka-Aki Koshimizu, Kenji Honda, Sachi Nagaoka-Uozumi, Atsuhiko Ichimura, Ikuo Kimura, Michio Nakaya, Nobuya Sakai, Katsushi Shibata, Kentarou Ushijima, Akio Fujimura, Akira Hirasawa, Hitoshi Kurose, Gozoh Tsujimoto, Akito Tanoue, Yukio Takano
Chronic morphine exposure upregulates adenylate cyclase signaling and reduces analgesic efficacy, a condition known as opioid tolerance. Nonopioid neurotransmitters can enhance morphine tolerance, but the mechanism for this is poorly understood. We show that morphine tolerance was delayed in mice lacking vasopressin 1b receptors (V1bRs) or after administration of V1bR antagonist into the rostral ventromedial medulla, where transcripts for V1bRs and μ-opioid receptors are co-localized. Vasopressin increased morphine-binding affinity in cells expressing both V1bR and μ-opioid receptors...
April 30, 2018: Nature Neuroscience
https://www.readbyqxmd.com/read/29710079/neurobiology-of-opioid-use-disorder-and-comorbid-traumatic-brain-injury
#20
Thomas R Kosten, David P Graham, David A Nielsen
Importance: Treating patients with opioid use disorder (OUD) and traumatic brain injury illustrates 6 neurobiological principles about the actions of 2 contrasting opioid analgesics, morphine and fentanyl, as well as pharmacotherapies for OUD, methadone, naltrexone, and buprenorphine. Observations: This literature review focused on a patient with traumatic brain injury who developed OUD from chronic morphine analgesia. His treatment is described in a neurobiological framework of 6 opioid action principles...
April 25, 2018: JAMA Psychiatry
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