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https://www.readbyqxmd.com/read/28087443/an-update-on-the-physiological-and-therapeutic-relevance-of-gpcr-oligomers
#1
REVIEW
Batoul Farran
The traditional view on GPCRs held that they function as single monomeric units composed of identical subunits. This notion was overturned by the discovery that GPCRs can form homo- and hetero-oligomers, some of which are obligatory, and can further assemble into receptor mosaics consisting of three or more protomers. Oligomerisation exerts significant impacts on receptor function and physiology, offering a platform for the diversification of receptor signalling, pharmacology, regulation, crosstalk, internalization and trafficking...
January 10, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28074535/gene-ages-nomenclatures-and-functional-diversification-of-the-methuselah-methuselah-like-gpcr-family-in-drosophila-and-tribolium
#2
REVIEW
Markus Friedrich, Jeffery W Jones
Affecting lifespan regulation and oxidative stress resistance, the G-protein coupled receptor (GPCR) gene methuselah (mth) plays important roles in the life history of Drosophila melanogaster. Substantial progress has been made in elucidating the molecular pathways by which mth affects these traits, yet conflicting ideas exist as to how old these genetic interactions are as well as how old the mth gene itself is. Root to these issues is the complex gene family history of the Mth/Mthl GPCR family, which experienced independent expansions in a variety of animal clades, leading to at least six subfamilies in insects...
January 11, 2017: Journal of Experimental Zoology. Part B, Molecular and Developmental Evolution
https://www.readbyqxmd.com/read/28074005/synergistic-regulation-of-serotonin-and-opioid-signaling-contributes-to-pain-insensitivity-in-nav1-7-knockout-mice
#3
Jörg Isensee, Leonhardt Krahé, Katharina Moeller, Vanessa Pereira, Jane E Sexton, Xiaohui Sun, Edward Emery, John N Wood, Tim Hucho
Genetic loss of the voltage-gated sodium channel Nav1.7 (Nav1.7(-/-)) results in lifelong insensitivity to pain in mice and humans. One underlying cause is an increase in the production of endogenous opioids in sensory neurons. We analyzed whether Nav1.7 deficiency altered nociceptive heterotrimeric guanine nucleotide-binding protein-coupled receptor (GPCR) signaling, such as initiated by GPCRs that respond to serotonin (pronociceptive) or opioids (antinociceptive), in sensory neurons. We found that the nociceptive neurons of Nav1...
January 10, 2017: Science Signaling
https://www.readbyqxmd.com/read/28073700/the-yeast-ste2p-g-protein-coupled-receptor-dimerizes-on-the-cell-plasma-membrane
#4
Orkun Cevheroğlu, Gözde Kumaş, Melinda Hauser, Jeffrey M Becker, Çağdaş D Son
Dimerization of G protein-coupled receptors (GPCR) may play an important role in maturation, internalization, signaling and/or pharmacology of these receptors. However, the location where dimerization occurs is still under debate. In our study, variants of Ste2p, a yeast mating pheromone GPCR, were tagged with split EGFP (enhanced green fluorescent protein) fragments inserted between transmembrane domain seven and the C-terminus or appended to the C-terminus. Bimolecular Fluorescence Complementation (BiFC) assay was used to determine where receptor dimerization occurred during protein trafficking by monitoring generation of EGFP fluorescence, which occurred upon GPCR dimerization...
January 7, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28073248/interplay-of-g-protein-coupled-receptors-with-the-membrane-insights-from-supra-atomic-coarse-grain-molecular-dynamics-simulations
#5
Xavier Periole
G protein-coupled receptors (GPCRs) are central to many fundamental cellular signaling pathways. They transduce signals from the outside to the inside of cells in physiological processes ranging from vision to immune response. It is extremely challenging to look at them individually using conventional experimental techniques. Recently, a pseudo atomistic molecular model has emerged as a valuable tool to access information on GPCRs, more specifically on their interactions with their environment in their native cell membrane and the consequences on their supramolecular organization...
January 11, 2017: Chemical Reviews
https://www.readbyqxmd.com/read/28063110/toward-the-next-step-in-g-protein-coupled-receptor-research-a-knowledge-driven-analysis-for-the-next-potential-targets-in-drug-discovery
#6
Koji Nagata, Yukie Katayama, Tomomi Sato, Yeondae Kwon, Takeshi Kawabata
More than 800 G protein-coupled receptor (GPCR) genes have been discovered in the human genome. Towards the next step in GPCR research, we performed a knowledge-driven analysis of orphan class-A GPCRs that may serve as novel targets in drug discovery. We examined the relationship between 61 orphan class-A GPCR genes and diseases using the Online Mendelian Inheritance in Man (OMIM) database and the DDSS tool. The OMIM database contains data on disease-related variants of the genes. Particularly, the variants of GPR101, GPR161, and GPR88 are related to the genetic diseases: growth hormone-secreting pituitary adenoma 2, pituitary stalk interruption syndrome (not confirmed), and childhood-onset chorea with psychomotor retardation, respectively...
January 6, 2017: Journal of Structural and Functional Genomics
https://www.readbyqxmd.com/read/28062602/methods-used-to-study-the-oligomeric-structure-of-g-protein-coupled-receptors
#7
Hui Guo, Su An, Richard J Ward, Yang Yang, Ying Liu, Xiao-Xi Guo, Qian Hao, Tian-Rui Xu
G-protein coupled receptors (GPCRs), which constitute the largest family of cell surface receptors, were originally thought to function as monomers, but are now recognized as being able to act in a wide range of oligomeric states and indeed, it is known that the oligomerization state of a GPCR can modulate its pharmacology and function. A number of experimental techniques have been devised to study GPCR oligomerization including those based upon traditional biochemistry such as blue-native polyacrylamide gel-electrophoresis (BN-PAGE), co-immunoprecipitation and protein-fragment complementation assays, those based upon resonance energy transfer, fluorescence resonance energy transfer (FRET), time-resolved FRET, FRET spectrometry and bioluminescence resonance energy transfer (BRET)...
January 6, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/28059859/pro-inflammatory-cytokines-mediate-gpcr-dysfunction
#8
Maradumane L Mohan, Neelakantan T Vasudevan, Sathyamangla V Naga Prasad
Pro-inflammatory reaction by the body occurs acutely in response to injury that is considered primarily beneficial. However, sustained pro-inflammatory cytokines observed with chronic pathologies such as metabolic syndrome, cancer, and arthritis are detrimental and in many cases is a major cardio-vascular risk factor. Pro-inflammatory cytokines such as interleulin-1 (IL-1), IL-6, and tumor necrosis factor α (TNFα) have long been implicated in cardiovascular risk and considered to be a major underlying cause for heart failure...
December 24, 2016: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/28059858/cardiac-gpcr-mediated-egfr-transactivation-impact-and-therapeutic-implications
#9
Laurel A Grisanti, Shuchi Guo, Douglas G Tilley
G protein-coupled receptors (GPCR) remain primary therapeutic targets for numerous cardiovascular disorders, including heart failure (HF), due to their influence on cardiac remodeling in response to elevated neurohormone signaling. GPCR blockers have proven to be beneficial in the treatment of HF by reducing chronic G protein activation and cardiac remodeling, thereby extending the lifespan of HF patients. Unfortunately this effect does not persist indefinitely, thus next generation therapeutics aim to selectively block harmful GPCR-mediated pathways while simultaneously promoting beneficial signaling...
January 3, 2017: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/28059140/identification-and-functional-characterisation-of-5-ht4-receptor-in-sea-cucumber-apostichopus-japonicus-selenka
#10
Tianming Wang, Zhen Yang, Naiming Zhou, Lina Sun, Zhenming Lv, Changwen Wu
Serotonin (5-HT) is an important neurotransmitter and neuromodulator that controls a variety of sensory and motor functions through 5-HT receptors (5-HTRs). The 5-HT4R subfamily is linked to Gs proteins, which activate adenylyl cyclases (ACs), and is involved in many responses in peripheral organs. In this study, the 5-HT4R from Apostichopus japonicus (Aj5-HT4R) was identified and characterised. The cloned full-length Aj5-HT4R cDNA is 1,544 bp long and contains an open reading frame 1,011 bp in length encoding 336 amino acid proteins...
January 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28049717/a-novel-hect-ubiquitin-ligase-regulating-chemotaxis-and-development-in-dictyostelium-discoideum
#11
Barbara Pergolizzi, Enrico Bracco, Salvatore Bozzaro
Cyclic AMP binding to G protein-coupled receptors orchestrates chemotaxis and development in Dictyostelium. By activating the RasC-TORC2-AKT/PKB module, cAMP regulates cell polarization during chemotaxis. TORC2 also mediates GPCR-dependent stimulation of adenylyl cyclase A (ACA), enhancing cAMP relay and developmental gene expression. Thus, mutants defective in the TORC2 Pia/Rictor subunit are impaired in chemotaxis and development. Near-saturation mutagenesis of a Pia/Rictor mutant by random gene disruption led to selection of two suppressor mutants, in which spontaneous chemotaxis and development were restored...
January 3, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28045251/a-g-protein-coupled-receptor-dimerization-interface-in-human-cone-opsins
#12
Beata Jastrzebska, William D Comar, Megan J Kaliszewski, Kevin C Skinner, Morgan H Torcasio, Anthony S Esway, Hui Jin, Krzysztof Palczewski, Adam W Smith
G protein-coupled receptors (GPCRs) detect a wide variety of physical and chemical signals and transmit that information across the cellular plasma membrane. Dimerization is a proposed modulator of GPCR signaling, but the structure and stability of class A GPCR dimerization have been difficult to establish. Here we investigated the dimerization affinity and binding interface of human cone opsins, which initiate and sustain daytime color vision. Using a time-resolved fluorescence approach, we found that human red cone opsin exhibits a strong propensity for dimerization, whereas the green and blue cone opsins do not...
November 29, 2016: Biochemistry
https://www.readbyqxmd.com/read/28040476/asp73-dependent-and-independent-regulation-of-the-affinity-of-ligands-for-human-histamine-h1-receptors-by-na
#13
Shigeru Hishinuma, Kiyoe Kosaka, Chizuru Akatsu, Yoshihiro Uesawa, Hiroyuki Fukui, Masaru Shoji
The affinity of ligands for G-protein-coupled receptors (GPCR) is allosterically regulated by Na(+) via a highly conserved aspartate residue (Asp(2.50)) in the second transmembrane domain of GPCRs. In the present study, we examined the Na(+)-mediated regulation of the affinity of ligands for Gq/11-protein-coupled human histamine H1 receptors in Chinese hamster ovary cells. The affinities of 3 agonists and 20 antihistamines were evaluated by their displacement curves against the binding of [(3)H]-mepyramine to membrane preparations in the presence or absence of 100 mM NaCl...
December 28, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28035083/us28-a-virally-encoded-gpcr-as-an-antiviral-target-for-human-cytomegalovirus-infection
#14
REVIEW
Sungjin Lee, Yoon Hee Chung, Choongho Lee
Viruses continue to evolve a new strategy to take advantage of every aspect of host cells in order to maximize their survival. Due to their central roles in transducing a variety of transmembrane signals, GPCRs seem to be a prime target for viruses to pirate for their own use. Incorporation of GPCR functionality into the genome of herpesviruses has been demonstrated to be essential for pathogenesis of many herpesviruses-induced diseases. Here, we introduce US28 of human cytomegalovirus (HCMV) as the beststudied example of virally-encoded GPCRs to manipulate host GPCR signaling...
January 1, 2017: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/28035080/multifactorial-regulation-of-g-protein-coupled-receptor-endocytosis
#15
REVIEW
Xiaohan Zhang, Kyeong-Man Kim
Endocytosis is a process by which cells absorb extracellular materials via the inward budding of vesicles formed from the plasma membrane. Receptor-mediated endocytosis is a highly selective process where receptors with specific binding sites for extracellular molecules internalize via vesicles. G protein-coupled receptors (GPCRs) are the largest single family of plasma-membrane receptors with more than 1000 family members. But the molecular mechanisms involved in the regulation of GPCRs are believed to be highly conserved...
January 1, 2017: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/28035079/biased-g-protein-coupled-receptor-signaling-new-player-in-modulating-physiology-and-pathology
#16
REVIEW
Zuzana Bologna, Jian-Peng Teoh, Ahmed S Bayoumi, Yaoliang Tang, Il-Man Kim
G protein-coupled receptors (GPCRs) are a family of cell-surface proteins that play critical roles in regulating a variety of pathophysiological processes and thus are targeted by almost a third of currently available therapeutics. It was originally thought that GPCRs convert extracellular stimuli into intracellular signals through activating G proteins, whereas β-arrestins have important roles in internalization and desensitization of the receptor. Over the past decade, several novel functional aspects of β-arrestins in regulating GPCR signaling have been discovered...
January 1, 2017: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/28034910/yeast-gpcr-signaling-reflects-the-fraction-of-occupied-receptors-not-the-number
#17
Alan Bush, Gustavo Vasen, Andreas Constantinou, Paula Dunayevich, Inés Lucía Patop, Matías Blaustein, Alejandro Colman-Lerner
According to receptor theory, the effect of a ligand depends on the amount of agonist-receptor complex. Therefore, changes in receptor abundance should have quantitative effects. However, the response to pheromone in Saccharomyces cerevisiae is robust (unaltered) to increases or reductions in the abundance of the G-protein-coupled receptor (GPCR), Ste2, responding instead to the fraction of occupied receptor. We found experimentally that this robustness originates during G-protein activation. We developed a complete mathematical model of this step, which suggested the ability to compute fractional occupancy depends on the physical interaction between the inhibitory regulator of G-protein signaling (RGS), Sst2, and the receptor...
December 29, 2016: Molecular Systems Biology
https://www.readbyqxmd.com/read/28034310/gaussian-accelerated-molecular-dynamics-in-namd
#18
Yui Tik Pang, Yinglong Miao, Yi Wang, J Andrew McCammon
Gaussian accelerated molecular dynamics (GaMD) is a recently developed enhanced sampling technique that provides efficient free energy calculations of biomolecules. Like the previous accelerated molecular dynamics (aMD), GaMD allows for "unconstrained" enhanced sampling without the need to set predefined collective variables and so is useful for studying complex biomolecular conformational changes such as protein folding and ligand binding. Furthermore, because the boost potential is constructed using a harmonic function that follows Gaussian distribution in GaMD, cumulant expansion to the second order can be applied to recover the original free energy profiles of proteins and other large biomolecules, which solves a long-standing energetic reweighting problem of the previous aMD method...
December 30, 2016: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28032980/ligand-discovery-for-a-peptide-binding-gpcr-by-structure-based-screening-of-fragment-and-lead-like-chemical-libraries
#19
Anirudh Ranganathan, Philipp Heine, Axel Rudling, Andreas Plückthun, Lutz Kummer, Jens Carlsson
Peptide-recognizing G protein-coupled receptors (GPCRs) are promising therapeutic targets, but often resist drug discovery efforts. Determination of crystal structures for peptide-binding GPCRs has provided opportunities to explore structure-based methods in lead development. Molecular docking screens of two chemical libraries, containing either fragment- or lead-like compounds, against a Neurotensin receptor 1 crystal structure allowed for a comparison between different drug development strategies for peptide-binding GPCRs...
December 29, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/28028940/capripox-outbreak-in-a-mixed-flock-of-sheep-and-goats-in-india
#20
M A Ramakrishnan, R Santhamani, A B Pandey
Generally, capripoxvirus infections are host specific in nature and occasionally infect more than one species. In this study, an investigation was carried out from an outbreak of capripox in a mixed flock of sheep and goats which occurred in 2013 in the State of Jammu & Kashmir. The genetic analysis of P32, RPO30 and GPCR genes revealed that both goats and sheep were infected with goatpox virus.
December 27, 2016: Transboundary and Emerging Diseases
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