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https://www.readbyqxmd.com/read/29149613/tuning-biased-gpcr-signaling-for-physiological-gain
#1
Skylar Spangler, Michael R Bruchas
Effective and safe doses of opiate painkillers, like morphine, can be limited by respiratory depression. Schmid et al. (2017) now present a quantitative method to design ligands and correlate GPCR signaling bias to the dose separation between therapeutic and adverse effects in animals.
November 16, 2017: Cell
https://www.readbyqxmd.com/read/29149605/bias-factor-and-therapeutic-window-correlate-to-predict-safer-opioid-analgesics
#2
Cullen L Schmid, Nicole M Kennedy, Nicolette C Ross, Kimberly M Lovell, Zhizhou Yue, Jenny Morgenweck, Michael D Cameron, Thomas D Bannister, Laura M Bohn
Biased agonism has been proposed as a means to separate desirable and adverse drug responses downstream of G protein-coupled receptor (GPCR) targets. Herein, we describe structural features of a series of mu-opioid-receptor (MOR)-selective agonists that preferentially activate receptors to couple to G proteins or to recruit βarrestin proteins. By comparing relative bias for MOR-mediated signaling in each pathway, we demonstrate a strong correlation between the respiratory suppression/antinociception therapeutic window in a series of compounds spanning a wide range of signaling bias...
November 16, 2017: Cell
https://www.readbyqxmd.com/read/29149024/the-role-of-the-mammalian-prion-protein-in-the-control-of-sleep
#3
REVIEW
Amber Roguski, Andrew C Gill
Sleep disruption is a prevalent clinical feature in many neurodegenerative disorders, including human prion diseases where it can be the defining dysfunction, as in the case of the "eponymous" fatal familial insomnia, or an early-stage symptom as in certain types of Creutzfeldt-Jakob disease. It is important to establish the role of the cellular prion protein (PrP(C)), the key molecule involved in prion pathogenesis, within the sleep-wake system in order to understand fully the mechanisms underlying its contribution to both healthy circadian rhythmicity and sleep dysfunction during disease...
November 17, 2017: Pathogens
https://www.readbyqxmd.com/read/29148820/a-functional-kinase-short-interfering-ribonucleic-acid-screen-using-protease-activated-receptor-2-dependent-opening-of-transient-receptor-potential-vanilloid-4
#4
William G Darby, Megan S Grace, Kaylene J Simpson, Owen L Woodman, Peter McIntyre
Protease-activated receptor 2 (PAR2) is a proinflammatory G-protein coupled receptor (GPCR) that is activated by inflammatory proteases, and its activation initiates signaling pathways that modulate the nonselective cation channel transient receptor potential vanilloid-4 (TRPV4). PAR2-dependent opening of TRPV4 has been attributed to kinase activation, but the identity of the responsible enzymes is unknown. Deciphering the signaling pathways involved in the PAR2-dependent opening of TRPV4 may yield new targets for pain treatment...
November 17, 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/29146594/heterologous-phosphorylation-induced-formation-of-a-stability-lock-permits-regulation-of-inactive-receptors-by-%C3%AE-arrestins
#5
András D Tóth, Susanne Prokop, Pál Gyombolai, Péter Várnai, András Balla, Vsevolod V Gurevich, László Hunyady, Gábor Turu
β-arrestins are key regulators and signal transducers of G protein-coupled receptors (GPCRs). The interaction between receptors and β-arrestins is generally believed to require both receptor activity and phosphorylation by GPCR kinases. In this study, we investigated whether β-arrestins are able to bind second messenger kinase-phosphorylated, but inactive receptors as well. Since heterologous phosphorylation is a common phenomenon among GPCRs, this mode of β-arrestin activation may represent a novel mechanism of signal transduction and receptor cross-talk...
November 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29146505/muscarinic-receptor-oligomerization
#6
REVIEW
Sara Marsango, Richard J Ward, Elisa Alvarez-Curto, Graeme Milligan
G protein coupled receptors (GPCRs) have been classically described as monomeric entities that function by binding in a 1:1 stoichiometric ratio to both ligand and downstream signalling proteins. However, in recent years, a growing numbers of studies have supported the hypothesis that these receptors can interact to form dimers and higher order oligomers although the molecular basis for these interactions, the overall quaternary arrangements and the functional importance of the GPCR oligomerization remain topics of intense speculation...
November 13, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/29146472/discovery-of-the-first-low-shift-positive-allosteric-modulators-for-the-muscarinic-m1-receptor
#7
Alexander Flohr, Roman Hutter, Barbara Mueller, Claudia Bohnert, Mélanie Pellisson, Hervé Schaffhauser
Positive modulation of the muscarinic M1-receptor has for a long time attracted scientists and drug developers for the potential treatment of Alzheimer's disease or Schizophrenia. The precognitive potential of M1 activation has however not been clinically demonstrated as a result of side effects associated both with agonists and positive allosteric modulators (PAM's) of the M1-receptor. To avoid excessive activation of the M1-receptor we have designed a new screening format and developed the first low-shift positive allosteric modulators for the M1 receptor...
November 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29144441/g-protein-coupled-receptors-targeted-by-analgesic-venom-peptides
#8
REVIEW
James T Daniel, Richard J Clark
Chronic pain is a complex and debilitating condition associated with a large personal and socioeconomic burden. Current pharmacological approaches to treating chronic pain such as opioids, antidepressants and anticonvulsants exhibit limited efficacy in many patients and are associated with dose-limiting side effects that hinder their clinical use. Therefore, improved strategies for the pharmacological treatment of pathological pain are urgently needed. G-protein coupled receptors (GPCRs) are ubiquitously expressed on the surface of cells and act to transduce extracellular signals and regulate physiological processes...
November 16, 2017: Toxins
https://www.readbyqxmd.com/read/29143784/primary-cilium-dependent-signaling-mechanisms
#9
REVIEW
Rajasekharreddy Pala, Nedaa Alomari, Surya M Nauli
Primary cilia are hair-like organelles and play crucial roles in vertebrate development, organogenesis, health, and many genetic disorders. A primary cilium is a mechano-sensory organelle that responds to mechanical stimuli in the micro-environment. A cilium is also a chemosensor that senses chemical signals surrounding a cell. The overall function of a cilium is therefore to act as a communication hub to transfer extracellular signals into intracellular responses. Although intracellular calcium has been one of the most studied signaling messengers that transmit extracellular signals into the cells, calcium signaling by various ion channels remains a topic of interest in the field...
October 28, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29142103/an-intracellular-activation-of-smoothened-independent-of-hedgehog-stimulation-in-drosophila
#10
Kai Jiang, Yajuan Liu, Jie Zhang, Jianhang Jia
Smoothened (Smo), a GPCR family protein, plays a critical role in the reception and transduction of Hedgehog (Hh) signal. Smo is phosphorylated and activated on the cell surface, however, it is unknown whether Smo can be intracellularly activated. Here, we demonstrate that inactivation of the ESCRT-III causes dramatic accumulation of Smo, and subsequent activation of Hh signaling. In contrast, inactivation of ESCRTs 0-II induces mild Smo accumulation. We provide evidence that Kurtz (Krz), the Drosophila β-arrestin2, acts in parallel with the ESCRTs 0-II pathway to sort Smo to the multivesicular bodies and lysosome-mediated degradation...
November 15, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/29141020/genomic-analysis-of-atypical-fibroxanthoma
#11
Kevin Lai, Catherine A Harwood, Karin J Purdie, Charlotte M Proby, Irene M Leigh, Namita Ravi, Thaddeus W Mully, Lionel Brooks, Priscilla M Sandoval, Michael D Rosenblum, Sarah T Arron
Atypical fibroxanthoma (AFX), is a rare type of skin cancer affecting older individuals with sun damaged skin. Since there is limited genomic information about AFX, our study seeks to improve the understanding of AFX through whole-exome and RNA sequencing of 8 matched tumor-normal samples. AFX is a highly mutated malignancy with recurrent mutations in a number of genes, including COL11A1, ERBB4, CSMD3, and FAT1. The majority of mutations identified were UV signature (C>T in dipyrimidines). We observed deletion of chromosomal segments on chr9p and chr13q, including tumor suppressor genes such as KANK1 and CDKN2A, but no gene fusions were found...
2017: PloS One
https://www.readbyqxmd.com/read/29136291/gpcr-signaling-from-intracellular-membranes-a-novel-concept
#12
Claudia Stäubert, Torsten Schöneberg
No abstract text is available yet for this article.
November 14, 2017: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/29133411/specific-inhibition-of-gpcr-independent-g-protein-signaling-by-a-rationally-engineered-protein
#13
Anthony Leyme, Arthur Marivin, Marcin Maziarz, Vincent DiGiacomo, Maria P Papakonstantinou, Prachi P Patel, Juan B Blanco-Canosa, Isha A Walawalkar, Gonzalo Rodriguez-Davila, Isabel Dominguez, Mikel Garcia-Marcos
Activation of heterotrimeric G proteins by cytoplasmic nonreceptor proteins is an alternative to the classical mechanism via G protein-coupled receptors (GPCRs). A subset of nonreceptor G protein activators is characterized by a conserved sequence named the Gα-binding and activating (GBA) motif, which confers guanine nucleotide exchange factor (GEF) activity in vitro and promotes G protein-dependent signaling in cells. GBA proteins have important roles in physiology and disease but remain greatly understudied...
November 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29131531/modifying-expression-modes-of-human-neurotensin-receptor-type-1-alters-sensing-capabilities-for-agonists-in-yeast-signaling-biosensor
#14
Hiroki Hashi, Yasuyuki Nakamura, Jun Ishii, Akihiko Kondo
Neurotensin receptor type 1 (NTSR1), a member of the G-protein-coupled receptor (GPCR) family, is naturally activated by binding of a neurotensin peptide, leading to a variety of physiological effects. The budding yeast Saccharomyces cerevisiae is a proven host organism for assaying the agonistic activation of human GPCRs. Previous studies showed that yeast cells can functionally express human NTSR1 receptor, permitting the detection of neurotensin-promoted signaling using a ZsGreen fluorescent reporter gene...
November 13, 2017: Biotechnology Journal
https://www.readbyqxmd.com/read/29126851/ccr6-signaling-inhibits-suppressor-function-of-induced-treg-during-gut-inflammation
#15
Neeraja Kulkarni, Heikrujam Thoihen Meitei, Sandip Ashok Sonar, Praveen Kumar Sharma, Vikkarasan Rehman Mujeeb, Sharad Srivastava, Ramanamurthy Boppana, Girdhari Lal
CCR6 is a G protein-coupled receptor (GPCR) that binds to a specific chemokine, CCL20. The role of CCR6-CCL20 is very well studied in the migration of immune cells, but the non-chemotaxis functions of CCR6 signaling were not known. Here, we show that during gut inflammation, the frequency of Foxp3(+)CD4(+) T cells (Tregs) reduced in the secondary lymphoid tissues and CCR6(+) Tregs enhanced the expression of RORγt. The peripheral blood mononuclear cells (PBMCs) of ulcerative colitis (UC) patients showed lower percentages of Foxp3(+)CD4(+) T cells, as compared to healthy individuals, with CCR6(+) Tregs showing higher RORγt expression as compared to CCR6(-)Tregs...
November 7, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/29123501/gonadotropin-releasing-hormone-gnrh-receptor-structure-and-gnrh-binding
#16
REVIEW
Colleen A Flanagan, Ashmeetha Manilall
Gonadotropin-releasing hormone (GnRH) regulates reproduction. The human GnRH receptor lacks a cytoplasmic carboxy-terminal tail but has amino acid sequence motifs characteristic of rhodopsin-like, class A, G protein-coupled receptors (GPCRs). This review will consider how recent descriptions of X-ray crystallographic structures of GPCRs in inactive and active conformations may contribute to understanding GnRH receptor structure, mechanism of activation and ligand binding. The structures confirmed that ligands bind to variable extracellular surfaces, whereas the seven membrane-spanning α-helices convey the activation signal to the cytoplasmic receptor surface, which binds and activates heterotrimeric G proteins...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/29116599/the-class-a-gpcr-dopamine-d2-receptor-forms-transient-dimers-stabilized-by-agonists-detection-by-single-molecule-tracking
#17
Rinshi S Kasai, Shuichi V Ito, Ryo M Awane, Takahiro K Fujiwara, Akihiro Kusumi
Whether class-A G-protein coupled receptors (GPCRs) exist and work as monomers or dimers has drawn extensive attention. A class-A GPCR dopamine D2 receptor (D2R) is involved in many physiological and pathological processes and diseases, indicating its critical role in proper functioning of neuronal circuits. In particular, D2R homodimers might play key roles in schizophrenia development and amphetamine-induced psychosis. Here, using single-molecule imaging, we directly tracked single D2R molecules in the plasma membrane at a physiological temperature of 37 °C, and unequivocally determined that D2R forms transient dimers with a lifetime of 68 ms in its resting state...
November 7, 2017: Cell Biochemistry and Biophysics
https://www.readbyqxmd.com/read/29116339/%C3%AE-arrestin-1-deficiency-ameliorates-renal-interstitial-fibrosis-by-blocking-wnt1-%C3%AE-catenin-signaling-in-mice
#18
Huiyan Xu, Quanxin Li, Jiang Liu, Jiaqing Zhu, Liang Li, Ziying Wang, Yan Zhang, Yu Sun, Jinpeng Sun, Rong Wang, Fan Yi
Despite substantial progress being made in understanding the mechanisms contributing to the pathogenesis of renal fibrosis, there are only a few therapies available to treat or prevent renal fibrosis in clinical use today. Therefore, identifying the key cellular and molecular mediators involved in the pathogenesis of renal fibrosis will provide new therapeutic strategy for treating patients with chronic kidney disease (CKD). β-Arrestin-1, a member of β-arrestin family, not only is a negative adaptor of G protein-coupled receptors (GPCRs), but also acts as a scaffold protein and regulates a diverse array of cellular functions independent of GPCR activation...
November 7, 2017: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/29113205/a-novel-method-to-identify-differential-pathways-in-uterine-leiomyomata-based-on-network-strategy
#19
Hui-Ling Wang, Jing Liu, Zhao-Min Qin
The aim of the present study was to identify differential pathways in uterine leiomyomata (UL) using a novel method based on protein-protein interaction networks and pathway analysis. The pathway networks were constructed by examining the intersections of the Reactome database and the Search Tool for the Retrieval of Interacting Genes/proteins (STRING) protein-protein interaction (PPI) networks. The Objective network was defined as the differential expressed genes (DEGs) associated with the interactions identified by STRING...
November 2017: Oncology Letters
https://www.readbyqxmd.com/read/29109685/binding-and-signaling-studies-disclose-a-potential-allosteric-site-for-cannabidiol-in-cannabinoid-cb2-receptors
#20
Eva Martínez-Pinilla, Katia Varani, Irene Reyes-Resina, Edgar Angelats, Fabrizio Vincenzi, Carlos Ferreiro-Vera, Julen Oyarzabal, Enric I Canela, José L Lanciego, Xavier Nadal, Gemma Navarro, Pier Andrea Borea, Rafael Franco
The mechanism of action of cannabidiol (CBD), the main non-psychotropic component of Cannabis sativa L., is not completely understood. First assumed that the compound was acting via cannabinoid CB2 receptors (CB2Rs) it is now suggested that it interacts with non-cannabinoid G-protein-coupled receptors (GPCRs); however, CBD does not bind with high affinity to the orthosteric site of any GPCR. To search for alternative explanations, we tested CBD as a potential allosteric ligand of CB2R. Radioligand and non-radioactive homogeneous binding, intracellular cAMP determination and ERK1/2 phosphorylation assays were undertaken in heterologous systems expressing the human version of CB2R...
2017: Frontiers in Pharmacology
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