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Lipid gpcr

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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
#1
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/27864940/endogenous-lpa1-receptor-agonists-demonstrate-ligand-bias-between-calcium-and-erk-signalling-pathways-in-human-lung-fibroblasts
#2
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/27851727/high-resolution-crystal-structure-of-the-human-cb1-cannabinoid-receptor
#3
Zhenhua Shao, Jie Yin, Karen Chapman, Magdalena Grzemska, Lindsay Clark, Junmei Wang, Daniel M Rosenbaum
The human cannabinoid G-protein-coupled receptors (GPCRs) CB1 and CB2 mediate the functional responses to the endocannabinoids anandamide and 2-arachidonyl glycerol (2-AG), as well as the widely consumed plant (phyto)cannabinoid Δ(9)-tetrahydrocannabinol (THC)(1). The cannabinoid receptors have been the targets of intensive drug discovery efforts owing to the therapeutic potential of modulators for controlling pain(2), epilepsy(3), obesity(4), and other maladies. Although much progress has recently been made in understanding the biophysical properties of GPCRs, investigations of the molecular mechanisms of the cannabinoids and their receptors have lacked high-resolution structural data...
November 16, 2016: Nature
https://www.readbyqxmd.com/read/27832814/obesity-induced-cardiac-lipid-accumulation-in-adult-mice-is-modulated-by-g-protein-coupled-receptor-kinase-2-levels
#4
Elisa Lucas, Rocio Vila-Bedmar, Alba C Arcones, Marta Cruces-Sande, Victoria Cachofeiro, Federico Mayor, Cristina Murga
BACKGROUND: The leading cause of death among the obese population is heart failure and stroke prompted by structural and functional changes in the heart. The molecular mechanisms that underlie obesity-related cardiac remodeling are complex, and include hemodynamic and metabolic alterations that ultimately affect the functionality of the myocardium. G protein-coupled receptor kinase 2 (GRK2) is an ubiquitous kinase able to desensitize the active form of several G protein-coupled receptors (GPCR) and is known to play an important role in cardiac GPCR modulation...
November 10, 2016: Cardiovascular Diabetology
https://www.readbyqxmd.com/read/27832490/adhesion-gpcrs-as-a-putative-class-of-metabotropic-mechanosensors
#5
Nicole Scholz, Kelly R Monk, Robert J Kittel, Tobias Langenhan
Adhesion GPCRs as mechanosensors. Different aGPCR homologs and their cognate ligands have been described in settings, which suggest that they function in a mechanosensory capacity. For details, see text G protein-coupled receptors (GPCRs) constitute the most versatile superfamily of biosensors. This group of receptors is formed by hundreds of GPCRs, each of which is tuned to the perception of a specific set of stimuli a cell may encounter emanating from the outside world or from internal sources. Most GPCRs are receptive for chemical compounds such as peptides, proteins, lipids, nucleotides, sugars, and other organic compounds, and this capacity is utilized in several sensory organs to initiate visual, olfactory, gustatory, or endocrine signals...
2016: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/27826255/membrane-mediated-oligomerization-of-g-protein-coupled-receptors-and-its-implications-for-gpcr-function
#6
REVIEW
Stefan Gahbauer, Rainer A Böckmann
The dimerization or even oligomerization of G protein coupled receptors (GPCRs) causes ongoing, controversial debates about its functional role and the coupled biophysical, biochemical or biomedical implications. A continously growing number of studies hints to a relation between oligomerization and function of GPCRs and strengthens the assumption that receptor assembly plays a key role in the regulation of protein function. Additionally, progress in the structural analysis of GPCR-G protein and GPCR-ligand interactions allows to distinguish between actively functional and non-signaling complexes...
2016: Frontiers in Physiology
https://www.readbyqxmd.com/read/27824122/real-time-monitoring-of-membrane-gpcr-reconstitution-by-plasmon-waveguide-resonance-on-the-role-of-lipids
#7
Pierre Calmet, Monica De Maria, Etienne Harté, Daniel Lamb, Maria Serrano-Vega, Ali Jazayeri, Nuska Tschammer, Isabel D Alves
G-protein coupled receptors (GPCRs) are important therapeutic targets since more than 40% of the drugs on the market exert their action through these proteins. To decipher the molecular mechanisms of activation and signaling, GPCRs often need to be isolated and reconstituted from a detergent-solubilized state into a well-defined and controllable lipid model system. Several methods exist to reconstitute membrane proteins in lipid systems but usually the reconstitution success is tested at the end of the experiment and often by an additional and indirect method...
November 8, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27812115/dynamic-cholesterol-conditioned-dimerization-of-the-g-protein-coupled-chemokine-receptor-type-4
#8
Kristyna Pluhackova, Stefan Gahbauer, Franziska Kranz, Tsjerk A Wassenaar, Rainer A Böckmann
G protein coupled receptors (GPCRs) allow for the transmission of signals across biological membranes. For a number of GPCRs, this signaling was shown to be coupled to prior dimerization of the receptor. The chemokine receptor type 4 (CXCR4) was reported before to form dimers and their functionality was shown to depend on membrane cholesterol. Here, we address the dimerization pattern of CXCR4 in pure phospholipid bilayers and in cholesterol-rich membranes. Using ensembles of molecular dynamics simulations, we show that CXCR4 dimerizes promiscuously in phospholipid membranes...
November 2016: PLoS Computational Biology
https://www.readbyqxmd.com/read/27726881/successful-strategies-to-determine-high-resolution-structures-of-gpcrs
#9
Jin Xiang, Eugene Chun, Chang Liu, Liang Jing, Zina Al-Sahouri, Lan Zhu, Wei Liu
G protein-coupled receptors (GPCRs) constitute the largest class of drug targets in the human genome, which highlights the importance of understanding the molecular basis of their activation, downstream signaling, and regulation. Since 2007, great progress has been made in the field of GPCR structure determination and their signaling complexes at the molecular level. Here, we summarize the high-resolution structures of over 30 different GPCRs with their co-crystallized ligands, and outline the successful strategies involved, including construct design, expression systems, and lipidic cubic phase (LCP) composition, and the many key technical parameters of the crystallization methods...
October 7, 2016: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/27687912/oxysterols-from-cholesterol-metabolites-to-key-mediators
#10
REVIEW
Valentin Mutemberezi, Owein Guillemot-Legris, Giulio G Muccioli
Oxysterols are cholesterol metabolites that can be produced through enzymatic or radical processes. They constitute a large family of lipids (i.e. the oxysterome) involved in a plethora of physiological processes. They can act through GPCR (e.g. EBI2, SMO, CXCR2), nuclear receptors (LXR, ROR, ERα) and through transporters or regulatory proteins. Their physiological effects encompass cholesterol, lipid and glucose homeostasis. Additionally, they were shown to be involved in other processes such as immune regulatory functions and brain homeostasis...
September 26, 2016: Progress in Lipid Research
https://www.readbyqxmd.com/read/27573285/regulatory-effects-of-grk2-on-gpcrs-and-non-gpcrs-and-possible-use-as-a-drug-target-review
#11
Chen-Chen Han, Yang Ma, Yifan Li, Yang Wang, Wei Wei
G protein-coupled receptor kinase 2 (GRK2) is a key member of the G protein-coupled receptor kinase (GRK) family. GRK2 activity is regulated by the C-terminus of GRK2 which contains a plekstrin homology domain and the N-terminus of GRK2 which contains the RGS homology domain with binding sites for several proteins and lipids such as G protein-coupled receptors (GPCRs), G protein, phospholipase C, phosphatidylinositol 4,5-bisphosphate, extracellular signal‑regulated kinase, protein kinase A and Gβγ...
October 2016: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/27544588/discovery-and-synthetic-optimization-of-a-novel-scaffold-for-hydrophobic-tunnel-targeted-autotaxin-inhibition
#12
Lauren E Ragle, Dilip J Palanisamy, Margaux J Joe, Rachel S Stein, Derek D Norman, Gabor Tigyi, Daniel L Baker, Abby L Parrill
Autotaxin (ATX) is a ubiquitous ectoenzyme that hydrolyzes lysophosphatidylcholine (LPC) to form the bioactive lipid mediator lysophosphatidic acid (LPA). LPA activates specific G-protein coupled receptors to elicit downstream effects leading to cellular motility, survival, and invasion. Through these pathways, upregulation of ATX is linked to diseases such as cancer and cardiovascular disease. Recent crystal structures confirm that the catalytic domain of ATX contains multiple binding regions including a polar active site, hydrophobic tunnel, and a hydrophobic pocket...
October 1, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27531651/coincident-signals-from-gpcrs-and-receptor-tyrosine-kinases-are-uniquely-transduced-by-pi3k%C3%AE-in-myeloid-cells
#13
Daniel M Houslay, Karen E Anderson, Tamara Chessa, Suhasini Kulkarni, Ralph Fritsch, Julian Downward, Jonathan M Backer, Len R Stephens, Phillip T Hawkins
Class I phosphoinositide 3-kinases (PI3Ks) catalyze production of the lipid messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3), which plays a central role in a complex signaling network regulating cell growth, survival, and movement. This network is overactivated in cancer and inflammation, and there is interest in determining the PI3K catalytic subunit (p110α, p110β, p110γ, or p110δ) that should be targeted in different therapeutic contexts. Previous studies have defined unique regulatory inputs for p110β, including direct interaction with Gβγ subunits, Rac, and Rab5...
2016: Science Signaling
https://www.readbyqxmd.com/read/27489943/functional-modulation-of-a-g-protein-coupled-receptor-conformational-landscape-in-a-lipid-bilayer
#14
Marina Casiraghi, Marjorie Damian, Ewen Lescop, Elodie Point, Karine Moncoq, Nelly Morellet, Daniel Levy, Jacky Marie, Eric Guittet, Jean-Louis Banères, Laurent J Catoire
Mapping the conformational landscape of G protein-coupled receptors (GPCRs), and in particular how this landscape is modulated by the membrane environment, is required to gain a clear picture of how signaling proceeds. To this end, we have developed an original strategy based on solution-state nuclear magnetic resonance combined with an efficient isotope labeling scheme. This strategy was applied to a typical GPCR, the leukotriene B4 receptor BLT2, reconstituted in a lipid bilayer. Because of this, we are able to provide direct evidence that BLT2 explores a complex landscape that includes four different conformational states for the unliganded receptor...
September 7, 2016: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/27474750/positive-and-negative-cross-talk-between-lysophosphatidic-acid-receptor-1-free-fatty-acid-receptor-4-and-epidermal-growth-factor-receptor-in-human-prostate-cancer-cells
#15
Mandi M Hopkins, Ze Liu, Kathryn E Meier
Lysophosphatidic acid (LPA) is a lipid mediator that mediates cellular effects via G protein-coupled receptors (GPCRs). Epidermal growth factor (EGF) is a peptide that acts via a receptor tyrosine kinase. LPA and EGF both induce proliferation of prostate cancer cells and can transactivate each other's receptors. The LPA receptor LPA1 is particularly important for LPA response in human prostate cancer cells. Previous work in our laboratory has demonstrated that free fatty acid 4 (FFA4), a GPCR activated by ω-3 fatty acids, inhibits responses to both LPA and EGF in these cells...
October 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27460867/the-molecular-mechanism-of-p2y1-receptor-activation
#16
Shuguang Yuan, H C Stephen Chan, Horst Vogel, Slawomir Filipek, Raymond C Stevens, Krzysztof Palczewski
Human purinergic G protein-coupled receptor P2Y1 (P2Y1 R) is activated by adenosine 5'-diphosphate (ADP) to induce platelet activation and thereby serves as an important antithrombotic drug target. Crystal structures of P2Y1 R revealed that one ligand (MRS2500) binds to the extracellular vestibule of this GPCR, whereas another (BPTU) occupies the surface between transmembrane (TM) helices TM2 and TM3. We introduced a total of 20 μs all-atom long-timescale molecular dynamic (MD) simulations to inquire why two molecules in completely different locations both serve as antagonists while ADP activates the receptor...
August 22, 2016: Angewandte Chemie
https://www.readbyqxmd.com/read/27418236/andrographolide-protects-liver-cells-from-h2o2-induced-cell-death-by-upregulation-of-nrf-2-ho-1-mediated-via-adenosine-a2a-receptor-signalling
#17
Smriti P K Mittal, Swati Khole, Nidhi Jagadish, Debjani Ghosh, Vijay Gadgil, Vilas Sinkar, Saroj S Ghaskadbi
BACKGROUND: Andrographolide, principle constituent of Andrographis paniculata Nees is used in traditional medicine in Southeast Asia and is known to exhibit various biological activities. Its antioxidant activity is due to its ability to activate one of the antioxidant enzymes, heme oxygenase-1 (HO-1) which is regulated transcriptionally through Nrf-2. However, molecular mechanism underlying activation of Nrf-2/HO-1 has not yet been clearly understood. METHODS: Protective effect of andrographolide against H2O2 induced cell death, reactive oxygen species and lipid peroxidation was observed in HepG2 cells...
November 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27354294/sphingosine-1-phosphate-signaling-impacts-lymphocyte-migration-inflammation-and-infection
#18
Irina V Tiper, James E East, Priyanka B Subrahmanyam, Tonya J Webb
Sphingosine 1-phosphate (S1P) is a sphingosine containing lipid intermediate obtained from ceramide. S1P is known to be an important signaling molecule and plays multiple roles in the context of immunity. This lysophospholipid binds and activates G-protein-coupled receptors (GPCRs) known as S1P receptors 1-5 (S1P1-5). Once activated, these GPCRs mediate signaling that can lead to alterations in cell proliferation, survival or migration, and can also have other effects such as promoting angiogenesis. In this review, we will present evidence demonstrating a role for S1P in lymphocyte migration, inflammation and infection, as well as in cancer...
August 2016: Pathogens and Disease
https://www.readbyqxmd.com/read/27318014/accelerated-molecular-dynamics-simulations-of-the-octopamine-receptor-using-gpus-discovery-of-an-alternate-agonist-binding-position
#19
Kevin W Kastner, Jesús A Izaguirre
Octopamine receptors (OARs) perform key biological functions in invertebrates, making this class of G-protein coupled receptors (GPCRs) worth considering for insecticide development. However, no crystal structures and very little research exists for OARs. Furthermore, GPCRs are large proteins, are suspended in a lipid bilayer, and are activated on the millisecond timescale, all of which make conventional molecular dynamics (MD) simulations infeasible, even if run on large supercomputers. However, accelerated Molecular Dynamics (aMD) simulations can reduce this timescale to even hundreds of nanoseconds, while running the simulations on graphics processing units (GPUs) would enable even small clusters of GPUs to have processing power equivalent to hundreds of CPUs...
October 2016: Proteins
https://www.readbyqxmd.com/read/27276266/the-functional-activity-of-the-human-serotonin-5-ht1a-receptor-is-controlled-by-lipid-bilayer-composition
#20
M Gertrude Gutierrez, Kylee S Mansfield, Noah Malmstadt
Although the properties of the cell plasma membrane lipid bilayer are broadly understood to affect integral membrane proteins, details of these interactions are poorly understood. This is particularly the case for the large family of G protein-coupled receptors (GPCRs). Here, we examine the lipid dependence of the human serotonin 5-HT1A receptor, a GPCR that is central to neuronal function. We incorporate the protein in synthetic bilayers of controlled composition together with a fluorescent reporting system that detects GPCR-catalyzed activation of G protein to measure receptor-catalyzed oligonucleotide exchange...
June 7, 2016: Biophysical Journal
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