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GPCR signaling

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https://www.readbyqxmd.com/read/27908835/modulation-of-signaling-through-gpcr-camp-pka-pathways-by-pde4-depends-on-stimulus-intensity-possible-implications-for-the-pathogenesis-of-acrodysostosis-without-hormone-resistance
#1
Emmanuelle Motte, Catherine Le Stunff, Claire Briet, Nicolas Dumaz, Caroline Silve
In acrodysostosis without hormone resistance, a disease caused by phosphodiesterase (PDE)-4D mutations, increased PDE activity leads to bone developmental defects but with normal renal responses to PTH. To identify potential mechanisms for these disparate responses, we compared the effect of PDE activity on hormone signaling through the GPCR-Gsα-cAMP-PKA pathway in cells from two lineages, HEK-293 cells stably overexpressing PTH1R (HEKpthr) and human dermal fibroblasts, including studies evaluating cAMP levels using an Epac-based BRET-sensor for cAMP (CAMYEL)...
November 28, 2016: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/27906555/ligand-biased-regulation-of-ptdins-3-4-5-p3-dependent-signal-transduction-in-gpcr-control-of-pituitary-hormone-release
#2
Joshua G Pemberton, John P Chang
Biased signaling describes the selective activation of signal transduction cascades by structurally-related ligands downstream of shared G protein-coupled receptors (GPCRs). Although class I phosphoinositide 3-kinases (PI3Ks) are important components of GPCR-controlled transduction networks, little is known regarding the potential for biased regulation of class I PI3K-dependent signaling. The full compliment of class I PI3K catalytic subunits (p110α, p110β, p110δ and p110γ) first appear in bony fishes and, despite being associated with distinct cellular functions, all class I PI3Ks produce the lipid second-messenger phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3)...
December 1, 2016: Endocrinology
https://www.readbyqxmd.com/read/27905105/endothelin-1-et-1-stimulates-carboxy-terminal-smad2-phosphorylation-in-vascular-endothelial-cells-by-a-mechanism-dependent-on-et-receptors-and-de-novo-protein-synthesis
#3
Narges Sharifat, Ghorban Mohammad Zadeh, Mohammad-Ali Ghaffari, Parisa Dayati, Danielle Kamato, Peter J Little, Hossein Babaahmadi-Rezaei
OBJECTIVE: G protein-coupled receptor (GPCR) agonists through their receptors can transactivate protein tyrosine kinase receptors such as epidermal growth factor receptor and serine/threonine kinase receptors most notably transforming growth factor (TGF)-β receptor (TβRI). This signalling mechanism represents a major expansion in the cellular outcomes attributable to GPCR signalling. This study addressed the role and mechanisms involved in GPCR agonist, endothelin-1 (ET-1)-mediated transactivation of the TβRI in bovine aortic endothelial cells (BAECs)...
December 1, 2016: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/27901063/regulation-of-%C3%AE-2b-adrenergic-receptor-cell-surface-transport-by-gga1-and-gga2
#4
Maoxiang Zhang, Wei Huang, Jie Gao, Alvin V Terry, Guangyu Wu
The molecular mechanisms that control the targeting of newly synthesized G protein-coupled receptors (GPCRs) to the functional destinations remain poorly elucidated. Here, we have determined the role of Golgi-localized, γ-adaptin ear domain homology, ADP ribosylation factor-binding proteins 1 and 2 (GGA1 and GGA2) in the cell surface transport of α2B-adrenergic receptor (α2B-AR), a prototypic GPCR, and studied the underlying mechanisms. We demonstrated that knockdown of GGA1 and GGA2 by shRNA and siRNA significantly reduced the cell surface expression of inducibly expressed α2B-AR and arrested the receptor in the perinuclear region...
November 30, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27899324/understanding-the-common-themes-and-diverse-roles-of-the-second-extracellular-loop-ecl2-of-the-gpcr-super-family
#5
Michael J Woolley, Alex C Conner
The extracellular loops (ECLs) of G protein-coupled receptors (GPCRs) can bind directly to docked orthosteric or allosteric ligands, they can contain transient contact points for ligand entry into the transmembrane (TM) bundle and they can regulate the activation of the receptor signalling pathways. Of the three ECLs, ECL2 is the largest and most structurally diverse reflecting its functional importance. This has been shown through biochemical techniques and has been supported by the many subsequent crystal structures of GPCRs bound to both agonists and antagonists...
November 26, 2016: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/27896950/ppar%C3%AE-agonists-negatively-regulate-%C3%AE-iib%C3%AE-3-integrin-outside-in-signalling-and-platelet-function-through-upregulation-of-protein-kinase-a-activity
#6
A J Unsworth, N Kriek, A P Bye, K Naran, T Sage, G D Flora, J M Gibbins
BACKGROUND: Agonists for the peroxisome proliferator activated receptor PPARγ, have been shown to have inhibitory effects on platelet activity following stimulation by GPVI and GPCR agonists. OBJECTIVES: Profound effects on thrombus formation led us to suspect a role for PPARγ agonists in the regulation of integrin αIIbβ3 mediated signalling. Both GPVI and GPCR signalling pathways lead to αIIbβ3 activation, and signalling through αIIbβ3 plays a critical role in platelet function and normal haemostasis...
November 29, 2016: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/27890725/functional-selectivity-at-g-protein-coupled-receptors-advancing-cannabinoid-receptors-as-drug-targets
#7
REVIEW
Srikrishnan Mallipeddi, David R Janero, Nikolai Zvonok, Alexandros Makriyannis
The phenomenon of functional selectivity, whereby a ligand preferentially directs the information output of a G-protein coupled receptor (GPCR) along (a) particular effector pathway(s) and away from others, has redefined traditional GPCR signaling paradigms to provide a new approach to structure-based drug design. The two principal cannabinoid receptors (CBRs) 1 and 2 belong to the class-A GPCR subfamily and are considered tenable therapeutic targets for several indications. Yet conventional orthosteric ligands (agonists, antagonists/inverse agonists) for these receptors have had very limited clinical utility due to their propensity to incite on-target adverse events...
November 24, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27889227/gpcr-signaling-and-trafficking-the-long-and-short-of-it
#8
REVIEW
Nathan J Pavlos, Peter A Friedman
Emerging findings disclose unexpected components of G protein-coupled receptor (GPCR) signaling and cell biology. Select GPCRs exhibit classical signaling, that is restricted to cell membranes, as well as newly described persistent signaling that depends on internalization of the GPCR bound to β-arrestins. Termination of non-canonical endosomal signaling requires intraluminal acidification and sophisticated protein trafficking machineries. Recent studies reveal the structural determinants of the trafficking chaperones...
November 23, 2016: Trends in Endocrinology and Metabolism: TEM
https://www.readbyqxmd.com/read/27888281/the-actions-of-relaxin-family-peptides-on-signal-transduction-pathways-activated-by-the-relaxin-family-peptide-receptor-rxfp4
#9
Sheng Y Ang, Dana S Hutchinson, Bronwyn A Evans, Mohammed A Hossain, Nitin Patil, Ross A D Bathgate, Martina Kocan, Roger J Summers
The relaxin family peptide receptor 4 (RXFP4) is a G protein-coupled receptor (GPCR) expressed in the colorectum with emerging roles in metabolism and appetite regulation. It is activated by its cognate ligand insulin-like peptide 5 (INSL5) that is expressed in enteroendocrine L cells in the gut. Whether other evolutionarily related peptides such as relaxin-2, relaxin-3, or INSL3 activate RXFP4 signal transduction mechanisms with a pattern similar to or distinct from INSL5 is still unclear. In this study, we compare the signaling pathways activated by various relaxin family peptides to INSL5...
November 26, 2016: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/27881485/visualization-of-ligand-induced-gi-protein-activation-in-chemotaxing-cells
#10
Kazuyuki Masuda, Jun-Ichi Kitakami, Tohru Kozasa, Tatsuhiko Kodama, Sigeo Ihara, Takao Hamakubo
Cell migration to chemoattractants is critically important in both normal physiology and the pathogenesis of many diseases. In GPCR-mediated chemotaxis, GPCRs transduce the gradient of an extracellular chemotactic ligand into intracellular responses via the activation of heterotrimeric G proteins. However, ligand-induced G protein activation has not been directly imaged as yet in mammalian chemotaxing cells. We developed a Förster resonance energy transfer (FRET) probe (R10-Gi) by linking the Gi protein α subunit to the regulator of G protein signaling domain...
November 23, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/27879340/gpcr-endocytosis-confers-uniformity-in-responses-to-chemically-distinct-ligands
#11
Nikoleta G Tsvetanova, Michelle Trester-Zedlitz, Billy W Newton, Daniel P Riordan, Aparna B Sundaram, Jeffrey R Johnson, Nevan J Krogan, Mark von Zastrow
The ability of chemically distinct ligands to produce different effects on the same G protein-coupled receptor (GPCR) has interesting therapeutic implications but, if excessively propagated downstream, would introduce biological 'noise' compromising cognate ligand detection. We asked if cells have the ability to limit the degree to which chemical diversity imposed at the ligand-GPCR interface is propagated to the downstream signal. We carried out an unbiased analysis of the integrated cellular response elicited by two chemically and pharmacodynamically diverse β-adrenoceptor agonists, isoproterenol and salmeterol...
November 22, 2016: Molecular Pharmacology
https://www.readbyqxmd.com/read/27875804/optogenetic-approaches-for-dissecting-neuromodulation-and-gpcr-signaling-in-neural-circuits
#12
REVIEW
Skylar M Spangler, Michael R Bruchas
Optogenetics has revolutionized neuroscience by providing means to control cell signaling with spatiotemporal control in discrete cell types. In this review, we summarize four major classes of optical tools to manipulate neuromodulatory GPCR signaling: opsins (including engineered chimeric receptors); photoactivatable proteins; photopharmacology through caging-photoswitchable molecules; fluorescent protein based reporters and biosensors. Additionally, we highlight technologies to utilize these tools in vitro and in vivo, including Cre dependent viral vector expression and two-photon microscopy...
November 19, 2016: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/27871651/erk-activated-by-histamine-h1-receptor-is-anti-proliferative-through-spatial-restriction-in-the-cytosol
#13
Ruchi Jain, Uchenna Watson, Deepak Kumar Saini
Histamine, a primary mediator of allergic responses, elicits its effects by activating specific receptors belonging to the GPCR family in target cells. Activation of histamine receptor can activate MAP kinases as recorded by monitoring the phosphorylation of extracellular signal regulated kinase (ERK). Despite this, ERK phosphorylation does not translate into pro-proliferative changes after histamine stimulation in HeLa cells. Here we show that histamine H1 receptor activation mediates MAPK activation through PLCβ, Src, PKCδ and MEK pathway, but does not lead to nuclear relocalization of phospho-ERK (pERK), classically associated with pro-proliferative changes...
October 25, 2016: European Journal of Cell Biology
https://www.readbyqxmd.com/read/27869740/functional-role-of-the-c-terminal-amphipathic-helix-8-of-olfactory-receptors-and-other-g-protein-coupled-receptors
#14
REVIEW
Takaaki Sato, Takashi Kawasaki, Shouhei Mine, Hiroyoshi Matsumura
G protein-coupled receptors (GPCRs) transduce various extracellular signals, such as neurotransmitters, hormones, light, and odorous chemicals, into intracellular signals via G protein activation during neurological, cardiovascular, sensory and reproductive signaling. Common and unique features of interactions between GPCRs and specific G proteins are important for structure-based design of drugs in order to treat GPCR-related diseases. Atomic resolution structures of GPCR complexes with G proteins have revealed shared and extensive interactions between the conserved DRY motif and other residues in transmembrane domains 3 (TM3), 5 and 6, and the target G protein C-terminal region...
November 18, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27865066/newly-synthesized-camp-is-integrated-at-a-membrane-protein-complex-signalosome-to-ensure-receptor-response-specificity
#15
Raquel Guinzberg, Antonio Díaz-Cruz, Carlos Acosta-Trujillo, María Magdalena Vilchis-Landeros, Héctor Vázquez-Meza, Carlos Lozano-Flores, Natalia Chiquete-Felix, Alfredo Varela-Echavarría, Salvador Uribe-Carvajal, Héctor Riveros-Rosas, Enrique Piña
Spatiotemporal regulation of cAMP within the cell is required to achieve receptor-specific responses. The mechanism through which the cell selects a specific response to new synthesized cAMP is not fully understood. In hepatocyte plasma membranes, we identified two functional and independent cAMP-responsive signaling protein macrocomplexes that produce, use, degrade, and regulate their own non-diffusible (sequestered) cAMP pool to achieve their specific responses. Each complex responds to the stimulation of an adenosine G-protein coupled receptor (Ado-GPCR), bound to either A2A or A2B , but not simultaneously to both...
November 19, 2016: FEBS Journal
https://www.readbyqxmd.com/read/27864940/endogenous-lpa1-receptor-agonists-demonstrate-ligand-bias-between-calcium-and-erk-signalling-pathways-in-human-lung-fibroblasts
#16
Afrah Sattikar, Mark R Dowling, Elizabeth M Rosethorne
BACKGROUND AND PURPOSE: Human lung fibroblasts (HLF) express high levels of the LPA1 receptor, a G protein-coupled receptor (GPCR) that responds to the endogenous lipid mediator lysophosphatidic acid (1-acyl-2-hydroxy-sn-glycero-3-phosphate; LPA). Several molecular species or analogues of LPA exist and have been detected in biological fluids such as serum and plasma. The most widely expressed of the LPA receptor family is the LPA1 receptor, which predominantly couples to Gq/11 , Gi/o and G12/13 proteins...
November 16, 2016: British Journal of Pharmacology
https://www.readbyqxmd.com/read/27860472/-cellular-and-molecular-mechanisms-of-action-of-bitter-compounds-recent-knowledge-and-perspective
#17
Milan Nagy, Pavel Mučaji
This overview paper describes in its introductory part bitter-tasting herbal drugs in the context of their traditional use in the loss of appetite and digestive disorders. Then, it mentions current knowledge on signals origin in bitter taste receptors leading to different, unexpected physiological processes. Newly observed biological effects of bitter tastants are correlated with modern trends of their complex study with an aim to develop new drugs primarily acting on bitter taste receptors.Key words: T2R bitter taste receptors GPCR bitters glucose homeostasis asthma ghrelin GLP-1 solitary chemosensory cells...
2016: Ceská a Slovenská Farmacie
https://www.readbyqxmd.com/read/27856640/g-protein-coupled-receptors-gpcrs-that-signal-via-protein-kinase-a-pka-cross-talk-at-insulin-receptor-substrate-1-irs1-to-activate-the-pi3k-akt-pathway
#18
Nathan C Law, Morris F White, Mary E Hunzicker-Dunn
GPCRs (G protein-coupled receptors)2 activate PI3K/AKT (phosphatidylinositol-3 kinase/v-AKT thymoma viral oncoprotein) to regulate many cellular functions that promote cell survival, proliferation, and growth. However, the mechanism by which GPCRs activate PI3K/AKT remains poorly understood. We used ovarian preantral granulosa cells (GCs) to elucidate the mechanism by which the GPCR agonist FSH (follicle-stimulating hormone) via PKA (protein kinase A) activates the PI3K/AKT cascade. IGF1 (insulin-like growth factor 1) is secreted in an autocrine/paracrine manner by GCs and activates the IGF1R (IGF1 receptor), but in the absence of FSH fails to stimulate YXXM phosphorylation of IRS1 (insulin receptor substrate 1) required for PI3K/AKT activation...
November 17, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27852822/targeted-elimination-of-g-proteins-and-arrestins-defines-their-specific-contributions-to-both-intensity-and-duration-of-g-protein-coupled-receptor-signalling
#19
Elisa Alvarez-Curto, Asuka Inoue, Laura Jenkins, Sheikh Zahir Raihan, Rudi Prihandoko, Andrew B Tobin, Graeme Milligan
G protein-coupled receptors (GPCRs) can initiate intracellular signalling cascades by coupling to an array of heterotrimeric G proteins and arrestin adaptor proteins. Understanding the contribution of each of these coupling options to GPCR signalling has been hampered by a paucity of tools to selectively perturb receptor function. Here we employ CRISPR/Cas9 genome editing to eliminate selected G proteins (Gαq and Gα11) or arrestin2 and arrestin3 from HEK293 cells, together with the elimination of receptor phosphorylation sites, to define the relative contribution of G proteins, arrestins and receptor phosphorylation to the signalling outcomes of the free fatty acid receptor 4 (FFA4)...
November 16, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27847172/novel-systematic-detergent-screening-method-for-membrane-proteins-solubilization
#20
Elodie Desuzinges Mandon, Morgane Agez, Rebecca Pellegrin, Sébastien Igonet, Anass Jawhari
Membrane proteins play crucial role in many cellular processes including cell adhesion, cell-cell communication, signal transduction and transport. To better understand the molecular basis of such central biological machines and in order to specifically study their biological and medical role, it is necessary to extract them from their membrane environment. To do so, it is challenging to find the best solubilization condition. Here we describe, a systematic screening method called BMSS (Biotinylated Membranes Solubilization & Separation) that allow screening 96 conditions at once...
November 12, 2016: Analytical Biochemistry
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