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https://www.readbyqxmd.com/read/27913310/targeted-disruption-of-the-orphan-receptor-gpr151-does-not-alter-pain-related-behaviour-despite-a-strong-induction-in-dorsal-root-ganglion-expression-in-a-model-of-neuropathic-pain
#1
Fiona E Holmes, Niall Kerr, Ying-Ju Chen, Penny Vanderplank, Craig A McArdle, David Wynick
BACKGROUND: Gpr151 is an orphan GPCR whose function is unknown. The restricted pattern of neuronal expression in the habenula, dorsal horn of the spinal cord and dorsal root ganglion plus homology with the galanin family of receptors imply a role in nociception. RESULTS: Real-time quantitative RT-PCR demonstrated a 49.9±2.9 fold highly significant (P<0.001) increase in Gpr151 mRNA expression in the dorsal root ganglion 7days after the spared nerve injury model of neuropathic pain...
November 29, 2016: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/27913115/computer-design-synthesis-and-bioactivity-analyses-of-drugs-like-fingolimod-used-in-the-treatment-of-multiple-sclerosis
#2
Gurbet Çelik Turgut, Doğukan Doyduk, Yılmaz Yıldırır, Serkan Yavuz, Atilla Akdemir, Ali Dişli, Alaattin Şen
Multiple sclerosis (MS) is a very common disease of vital importance. In the MS treatment, some drugs such as fingolimod which help to protect nerves from damage are used. The main goal of the drug therapy in MS is to take control of the inflammation which leads to the destruction of myelin and axons in nerve cell and thus prevent and stop the progression of the disease. Fingolimod (FTY720) is an orally active immunomodulatory drug that has been used for the treatment of relapsing-remitting multiple sclerosis...
November 18, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27911814/distinct-cortical-and-striatal-actions-of-a-%C3%AE-arrestin-biased-dopamine-d2-receptor-ligand-reveal-unique-antipsychotic-like-properties
#3
Nikhil M Urs, Steven M Gee, Thomas F Pack, John D McCorvy, Tama Evron, Joshua C Snyder, Xiaobao Yang, Ramona M Rodriguiz, Emiliana Borrelli, William C Wetsel, Jian Jin, Bryan L Roth, Patricio O'Donnell, Marc G Caron
The current dopamine (DA) hypothesis of schizophrenia postulates striatal hyperdopaminergia and cortical hypodopaminergia. Although partial agonists at DA D2 receptors (D2Rs), like aripiprazole, were developed to simultaneously target both phenomena, they do not effectively improve cortical dysfunction. In this study, we investigate the potential for newly developed β-arrestin2 (βarr2)-biased D2R partial agonists to simultaneously target hyper- and hypodopaminergia. Using neuron-specific βarr2-KO mice, we show that the antipsychotic-like effects of a βarr2-biased D2R ligand are driven through both striatal antagonism and cortical agonism of D2R-βarr2 signaling...
December 1, 2016: Proceedings of the National Academy of Sciences of the United States of America
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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/27882567/autoantibodies-directed-against-the-endothelin-a-receptor-in-patients-with-benign-prostatic-hyperplasia
#13
Gerd Wallukat, Burkhard Jandrig, Rudolf Kunze, Johann J Wendler, Johannes Müller, Martin Schostak, Ingolf Schimke
BACKGROUND: Over-stimulation of G-protein coupled receptors (GPCRs) such as α1-adrenergic, muscarinic, endothelin, and AT1 receptors is considered to drive benign prostatic hyperplasia (BHP) which is often associated with lower urinary tract syndrome (LUTS). However, in addition to physiologic GPCR ligands, there is a new class of autoantibodies called functional autoantibodies that target the same GPCRs (GPCR-AABs) for over-stimulation, thus, presenting pathogenic potency. We hypothesize that patients with BPH/LUTS could carry GPCR-AABs representing potential targets for treatment...
November 24, 2016: Prostate
https://www.readbyqxmd.com/read/27881485/visualization-of-ligand-induced-gi-protein-activation-in-chemotaxing-cells
#14
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
#15
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
#16
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/27874067/5-htr3-and-5-htr4-located-on-the-mitochondrial-membrane-and-functionally-regulated-mitochondrial-functions
#17
Qingyi Wang, Huiyuan Zhang, Hao Xu, Dongqing Guo, Hui Shi, Yuan Li, Weiwei Zhang, Yuchun Gu
5-HT has been reported to possess significant effects on cardiac activities, but activation of 5-HTR on the cell membrane failed to illustrate the controversial cardiac reaction. Because 5-HT constantly comes across the cell membrane via 5-HT transporter (5-HTT) into the cytoplasm, whether 5-HTR is functional present on the cellular organelles is unknown. Here we show 5-HTR3 and 5-HTR4 were located in cardiac mitochondria, and regulated mitochondrial activities and cellular functions. Knock down 5-HTR3 and 5-HTR4 in neonatal cardiomyocytes resulted in significant increase of cell damage in response to hypoxia, and also led to alternation in heart beating...
November 22, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27871651/erk-activated-by-histamine-h1-receptor-is-anti-proliferative-through-spatial-restriction-in-the-cytosol
#18
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/27871057/mechanistic-insights-into-gpcr-g-protein-interactions
#19
REVIEW
Jacob P Mahoney, Roger K Sunahara
G protein-coupled receptors (GPCRs) respond to extracellular stimuli and interact with several intracellular binding partners to elicit cellular responses, including heterotrimeric G proteins. Recent structural and biophysical studies have highlighted the dynamic nature of GPCRs and G proteins and have identified specific conformational changes important for receptor-mediated nucleotide exchange on Gα. While domain separation within Gα is necessary for GDP release, opening the inter-domain interface is insufficient to stimulate nucleotide exchange...
November 18, 2016: Current Opinion in Structural Biology
https://www.readbyqxmd.com/read/27870241/multiple-parameter-optimization-in-drug-discovery-example-of-the-5-ht1b-gpcr
#20
Robert Charles Glen, Warren R J D Galloway, David R Spring, Gemma Liwiki
Early phase drug discovery is a multi-parameter optimisation process. Finding drugable targets, discovering starting points for lead optimisation and creating novel structures with new biological properties within these constraints is challenging. As an example of a drug optimisation strategy, recent work on 5-HT1B antagonists will be described. This is put in the context of the drugability of the target, the desired physicochemical properties of the desired molecules and approaches to compound design to create high affinity, selective molecules that are optimised to have low Central Nervous System (CNS) penetration...
December 2016: Molecular Informatics
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