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https://www.readbyqxmd.com/read/29334381/the-molecular-basis-of-subtype-selectivity-of-human-kinin-g-protein-coupled-receptors
#1
Lisa Joedicke, Jiafei Mao, Georg Kuenze, Christoph Reinhart, Tejaswi Kalavacherla, Hendrik R A Jonker, Christian Richter, Harald Schwalbe, Jens Meiler, Julia Preu, Hartmut Michel, Clemens Glaubitz
G-protein-coupled receptors (GPCRs) are the most important signal transducers in higher eukaryotes. Despite considerable progress, the molecular basis of subtype-specific ligand selectivity, especially for peptide receptors, remains unknown. Here, by integrating DNP-enhanced solid-state NMR spectroscopy with advanced molecular modeling and docking, the mechanism of the subtype selectivity of human bradykinin receptors for their peptide agonists has been resolved. The conserved middle segments of the bound peptides show distinct conformations that result in different presentations of their N and C termini toward their receptors...
January 15, 2018: Nature Chemical Biology
https://www.readbyqxmd.com/read/29330504/unique-roles-of-%C3%AE-arrestin-in-gpcr-trafficking-revealed-by-photoinducible-dimerizers
#2
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
https://www.readbyqxmd.com/read/29330286/agonist-induced-cxcr4-and-cb2-heterodimerization-inhibits-g%C3%AE-13-rhoa-mediated-migration
#3
Kisha A Scarlett, ElShaddai Z White, Christopher J Coke, Jada R Carter, Latoya K Bryant, Cimona V Hinton
G-protein coupled receptor (GPCR) heterodimerization has emerged as a means by which alternative signaling entities can be created; yet, how receptor heterodimers affect receptor pharmacology remains unknown. Previous observations suggested a biochemical antagonism between GPCRs, CXCR4 and CB2 (CNR2), where agonist-bound CXCR4 and agonist-bound CB2 formed a physiologically non-functional heterodimer on the membrane of cancer cells, inhibiting their metastatic potential in vitro. However, the reduced signaling entities responsible for the observed functional outputs remain elusive...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29326051/-investigation-methods-to-explore-g-protein-coupled-receptor-regulated-translatome
#4
Aurélie Tréfier, Florian Guillou, Pascale Crépieux
With the advent of next-generation sequencing technologies, identifying the translatome, which includes genome-wide ribosome-associated mRNAs, provides new opportunities to define faithfully the protein repertoire of a cell, as opposed to transcriptomic approaches. In addition, the role that extracellular signals such as hormonal modulations could play on the translatome remains to be deciphered. In particular, the regulation of the translatome by G protein-coupled receptors (GPCR) is still poorly described, albeit the trophic role that many receptors of this family play in their target cells...
January 8, 2018: Comptes Rendus Biologies
https://www.readbyqxmd.com/read/29323277/structure-and-dynamics-of-gpcr-signaling-complexes
#5
REVIEW
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
https://www.readbyqxmd.com/read/29302067/biased-signalling-from-simple-switches-to-allosteric-microprocessors
#6
REVIEW
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
https://www.readbyqxmd.com/read/29301490/molecular-characterization-of-larval-development-from-fertilization-to-metamorphosis-in-a-reef-building-coral
#7
Marie E Strader, Galina V Aglyamova, Mikhail V Matz
BACKGROUND: Molecular mechanisms underlying coral larval competence, the ability of larvae to respond to settlement cues, determine their dispersal potential and are potential targets of natural selection. Here, we profiled competence, fluorescence and genome-wide gene expression in embryos and larvae of the reef-building coral Acropora millepora daily throughout 12 days post-fertilization. RESULTS: Gene expression associated with competence was positively correlated with transcriptomic response to the natural settlement cue, confirming that mature coral larvae are "primed" for settlement...
January 4, 2018: BMC Genomics
https://www.readbyqxmd.com/read/29298905/gliotransmission-beyond-black-and-white
#8
Iaroslav Savtchouk, Andrea Volterra
Astrocytes are highly complex cells with many emerging putative roles in brain function. Of these, gliotransmission (active information transfer from glia to neurons) has probably the widest implications on our understanding of how the brain works: do astrocytes really contribute to information processing within the neural circuitry? "Positive evidence" for this stems from work of multiple laboratories reporting many examples of modulatory chemical signaling from astrocytes to neurons in the timeframe of hundreds of milliseconds to several minutes...
January 3, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29298426/interrogating-the-spatiotemporal-landscape-of-neuromodulatory-gpcr-signaling-by-real-time-imaging-of-camp-in-intact-neurons-and-circuits
#9
Brian S Muntean, Stefano Zucca, Courtney M MacMullen, Maria T Dao, Caitlin Johnston, Hideki Iwamoto, Randy D Blakely, Ronald L Davis, Kirill A Martemyanov
Modulation of neuronal circuits is key to information processing in the brain. The majority of neuromodulators exert their effects by activating G-protein-coupled receptors (GPCRs) that control the production of second messengers directly impacting cellular physiology. How numerous GPCRs integrate neuromodulatory inputs while accommodating diversity of incoming signals is poorly understood. In this study, we develop an in vivo tool and analytical suite for analyzing GPCR responses by monitoring the dynamics of a key second messenger, cyclic AMP (cAMP), with excellent quantitative and spatiotemporal resolution in various neurons...
January 2, 2018: Cell Reports
https://www.readbyqxmd.com/read/29290469/allosteric-coupling-of-drug-binding-and-intracellular-signaling-in-the-a2a-adenosine-receptor
#10
Matthew T Eddy, Ming-Yue Lee, Zhan-Guo Gao, Kate L White, Tatiana Didenko, Reto Horst, Martin Audet, Pawel Stanczak, Kyle M McClary, Gye Won Han, Kenneth A Jacobson, Raymond C Stevens, Kurt Wüthrich
Signaling across cellular membranes, the 826 human G protein-coupled receptors (GPCRs) govern a wide range of vital physiological processes, making GPCRs prominent drug targets. X-ray crystallography provided GPCR molecular architectures, which also revealed the need for additional structural dynamics data to support drug development. Here, nuclear magnetic resonance (NMR) spectroscopy with the wild-type-like A2A adenosine receptor (A2AAR) in solution provides a comprehensive characterization of signaling-related structural dynamics...
December 27, 2017: Cell
https://www.readbyqxmd.com/read/29290039/evidence-of-g-protein-coupled-receptor-and-substrate-transporter-heteromerization-at-a-single-molecule-level
#11
Jana Fischer, Gunnar Kleinau, Claudia Rutz, Denise Zwanziger, Noushafarin Khajavi, Anne Müller, Maren Rehders, Klaudia Brix, Catherine L Worth, Dagmar Führer, Heiko Krude, Burkhard Wiesner, Ralf Schülein, Heike Biebermann
G-protein-coupled receptors (GPCRs) can constitute complexes with non-GPCR integral membrane proteins, while such interaction has not been demonstrated at a single molecule level so far. We here investigated the potential interaction between the thyrotropin receptor (TSHR) and the monocarboxylate transporter 8 (MCT8), a member of the major facilitator superfamily (MFS), using fluorescence cross-correlation spectroscopy (FCCS). Both the proteins are expressed endogenously on the basolateral plasma membrane of the thyrocytes and are involved in stimulation of thyroid hormone production and release...
December 30, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/29279314/microtubule-regulation-of-kv7-channels-orchestrates-camp-mediated-vasorelaxations-in-rat-arterial-smooth-muscle
#12
Johanna Lindman, Makhala M Khammy, Pia R Lundegaard, Christian Aalkjær, Thomas A Jepps
Microtubules can regulate GPCR (G protein-coupled receptor) signaling in various cell types. In vascular smooth muscle, activation of the β-adrenoceptor leads to production of cAMP to mediate a vasorelaxation. Little is known about the role of microtubules in smooth muscle, and given the importance of this pathway in vascular smooth muscle cells, we investigated the role of microtubule stability on β-adrenoceptor signaling in rat renal and mesenteric arteries. In isometric tension experiments, incubation with the microtubule inhibitors colchicine and nocodazole enhanced isoprenaline-mediated relaxations of renal and mesenteric arteries that the microtubule stabilizer, paclitaxel, prevented...
December 26, 2017: Hypertension
https://www.readbyqxmd.com/read/29277445/biased-g-protein-coupled-receptor-agonism-mediates-neu1-sialidase-and-matrix-metalloproteinase-9-crosstalk-to-induce-transactivation-of-insulin-receptor-signaling
#13
Fiona Haxho, Sabah Haq, Myron R Szewczuk
G protein-coupled receptors (GPCR) can participate in a number of signaling pathways, and this property led to the concept of biased GPCR agonism. Agonists, antagonists and allosteric modulators can bind to GPCRs in different ways, creating unique conformations that differentially modulate signaling through one or more G proteins. A unique neuromedin B (NMBR) GPCR-signaling platform controlling mammalian neuraminidase-1 (Neu1) and matrix metalloproteinase-9 (MMP9) crosstalk has been reported in the activation of the insulin receptor (IR) through the modification of the IR glycosylation...
December 24, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/29277246/studying-gpcr-pharmacology-in-membrane-microdomains-fluorescence-correlation-spectroscopy-comes-of-age
#14
REVIEW
Stephen J Briddon, Laura E Kilpatrick, Stephen J Hill
G protein-coupled receptors (GPCRs) are organised within the cell membrane into highly ordered macromolecular complexes along with other receptors and signalling proteins. Understanding how heterogeneity in these complexes affects the pharmacology and functional response of these receptors is crucial for developing new and more selective ligands. Fluorescence correlation spectroscopy (FCS) and related techniques such as photon counting histogram (PCH) analysis and image-based FCS can be used to interrogate the properties of GPCRs in these membrane microdomains, as well as their interaction with fluorescent ligands...
December 22, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/29276072/fluorescence-approaches-unravel-spatial-and-temporal-aspects-of-gpcr-organisation-location-and-intracellular-signalling
#15
EDITORIAL
Stephen J Hill, Stephen P Watson
No abstract text is available yet for this article.
December 21, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/29249810/schizophrenia-and-depression-two-poles-of-endocannabinoid-system-deregulation
#16
María Rodríguez-Muñoz, Pilar Sánchez-Blázquez, Luis F Callado, J Javier Meana, Javier Garzón-Niño
The activity of certain G protein-coupled receptors (GPCRs) and of glutamate N-Methyl-D-aspartate receptors (NMDARs) is altered in both schizophrenia and depression. Using postmortem prefrontal cortex samples from subjects with schizophrenia or depression, we observed a series of opposite changes in the expression of signaling proteins that have been implicated in the cross-talk between GPCRs and NMDARs. Thus, the levels of HINT1 proteins and NMDAR NR1 subunits carrying the C1 cytosolic segment were increased in depressives and decreased in schizophrenics, respect to matched controls...
December 18, 2017: Translational Psychiatry
https://www.readbyqxmd.com/read/29249607/intracellular-transfer-of-na-in-an-active-state-g-protein-coupled-receptor
#17
Owen N Vickery, Catarina A Carvalheda, Saheem A Zaidi, Andrei V Pisliakov, Vsevolod Katritch, Ulrich Zachariae
Playing a central role in cell signaling, G-protein-coupled receptors (GPCRs) are the largest superfamily of membrane proteins and form the majority of drug targets in humans. How extracellular agonist binding triggers the activation of GPCRs and associated intracellular effector proteins remains, however, poorly understood. Structural studies have revealed that inactive class A GPCRs harbor a conserved binding site for Na+ ions in the center of their transmembrane domain, accessible from the extracellular space...
December 6, 2017: Structure
https://www.readbyqxmd.com/read/29248440/jtc801-induces-ph-dependent-death-specifically-in-cancer-cells-and-slows-growth-of-tumors-in-mice
#18
Xinxin Song, Shan Zhu, Yangchun Xie, Jiao Liu, Lingyi Sun, Dexing Zeng, Pengcheng Wang, Xiaochao Ma, Guido Kroemer, David L Bartlett, Timothy R Billiar, Michael Lotze, Herbert Zeh, Rui Kang, Daolin Tang
BACKGROUND & AIMS: Maintenance of acid-base homeostasis is required for normal physiology, metabolism, and development. It is not clear how cell death is activated in response to changes in pH. We performed a screen to identify agents that induce cell death in a pH-dependent manner (we call this alkaliptosis) in pancreatic ductal adenocarcinoma cancer (PDAC) cells and tested their effects in mice. METHODS: We screened a library of 254 compounds that interact with G protein-coupled receptors (GPCRs) to identify those with cytotoxic activity against a human PDAC cell line (PANC1)...
December 14, 2017: Gastroenterology
https://www.readbyqxmd.com/read/29240722/g-protein-coupled-receptors-at-the-crossroad-between-physiologic-and-pathologic-angiogenesis-old-paradigms-and-emerging-concepts
#19
REVIEW
Ernestina M De Francesco, Federica Sotgia, Robert B Clarke, Michael P Lisanti, Marcello Maggiolini
G protein-coupled receptors (GPCRs) have been implicated in transmitting signals across the extra- and intra-cellular compartments, thus allowing environmental stimuli to elicit critical biological responses. As GPCRs can be activated by an extensive range of factors including hormones, neurotransmitters, phospholipids and other stimuli, their involvement in a plethora of physiological functions is not surprising. Aberrant GPCR signaling has been regarded as a major contributor to diverse pathologic conditions, such as inflammatory, cardiovascular and neoplastic diseases...
December 14, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29239726/camp-signaling-regulates-dna-hydroxymethylation-by-augmenting-the-intracellular-labile-ferrous-iron-pool
#20
Vladimir Camarena, David W Sant, Tyler C Huff, Sushmita Mustafi, Ryan K Muir, Allegra T Aron, Christopher J Chang, Adam R Renslo, Paula V Monje, Gaofeng Wang
It is widely accepted that cAMP regulates gene transcription principally by activating the protein kinase A (PKA)-targeted transcription factors. Here, we show that cAMP enhances the generation of 5-hydroxymethylcytosine (5hmC) in multiple cell types. 5hmC is converted from 5-methylcytosine (5mC) by Tet methylcytosine dioxygenases, for which Fe(II) is an essential cofactor. The promotion of 5hmC was mediated by a prompt increase of the intracellular labile Fe(II) pool (LIP). cAMP enhanced the acidification of endosomes for Fe(II) release to the LIP likely through RapGEF2...
December 14, 2017: ELife
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