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https://www.readbyqxmd.com/read/28535146/role-of-spatial-inhomogenity-in-gpcr-dimerisation-predicted-by-receptor-association-diffusion-models
#1
Sneha A Deshpande, Aiswarya B Pawar, Anish Dighe, Chaitanya A Athale, Durba Sengupta
G protein-coupled receptor (GPCR) association is an emerging paradigm with far reaching implications in the regulation of signalling pathways and therapeutic interventions. Recent super resolution microscopy studies have revealed that receptor dimer steady state exhibits sub-second dynamics. In particular the GPCRs, muscarinic acetylcholine receptor M1 (M1MR) and formyl peptide receptor (FPR), have been demonstrated to exhibit a fast association/dissociation kinetics, independent of ligand binding. In this work, we have developed a spatial kinetic Monte Carlo model to investigate receptor homo-dimerisation at a single receptor resolution...
May 23, 2017: Physical Biology
https://www.readbyqxmd.com/read/28533165/analgesic-conopeptides-targeting-g-protein-coupled-receptors-reduce-excitability-of-sensory-neurons
#2
REVIEW
Mahsa Sadeghi, Jeffrey R McArthur, Rocio K Finol-Urdaneta, David J Adams
Conotoxins (conopeptides) are a diverse group of peptides isolated from the venom of marine cone snails. Conus peptides modulate pain by interacting with voltage-gated ion channels and G protein-coupled receptors (GPCRs). Opiate drugs targeting GPCRs have long been used, nonetheless, many undesirable side effects associated with opiates have been observed including addiction. Consequently, alternative avenues to pain management are a largely unmet need. It has been shown that various voltage-gated calcium channels (VGCCs) respond to GPCR modulation...
May 19, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28528660/pleiotropic-gpcr-signaling-in-health-and-disease
#3
EDITORIAL
Aylin C Hanyaloglu, Dimitris K Grammatopoulos
No abstract text is available yet for this article.
July 5, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28524165/molecular-assembly-of-rhodopsin-with-g-protein-coupled-receptor-kinases
#4
Yuanzheng He, Xiang Gao, Devrishi Goswami, Li Hou, Kuntal Pal, Yanting Yin, Gongpu Zhao, Oliver P Ernst, Patrick Griffin, Karsten Melcher, H Eric Xu
G protein-coupled receptor kinases (GRKs) play pivotal roles in desensitizing GPCR signaling but little is known about how GRKs recognize and phosphorylate GPCRs due to the technical difficulties in detecting the highly dynamic GPCR/GRK interaction. By combining a genetic approach with multiple biochemical assays, we identified the key determinants for the assembly of the prototypical GPCR rhodopsin with its kinase GRK1. Our work reveals that the regulatory G-protein signaling homology (RH) domain of GRKs is the primary binding site to GPCRs and an active conformation of the GRK1 kinase domain is required for efficient interaction with rhodopsin...
May 19, 2017: Cell Research
https://www.readbyqxmd.com/read/28516903/molecular-mechanism-of-g%C3%AE-i-activation-by-non-gpcr-proteins-with-a-g%C3%AE-binding-and-activating-motif
#5
Alain Ibáñez de Opakua, Kshitij Parag-Sharma, Vincent DiGiacomo, Nekane Merino, Anthony Leyme, Arthur Marivin, Maider Villate, Lien T Nguyen, Miguel Angel de la Cruz-Morcillo, Juan B Blanco-Canosa, Sekar Ramachandran, George S Baillie, Richard A Cerione, Francisco J Blanco, Mikel Garcia-Marcos
Heterotrimeric G proteins are quintessential signalling switches activated by nucleotide exchange on Gα. Although activation is predominantly carried out by G-protein-coupled receptors (GPCRs), non-receptor guanine-nucleotide exchange factors (GEFs) have emerged as critical signalling molecules and therapeutic targets. Here we characterize the molecular mechanism of G-protein activation by a family of non-receptor GEFs containing a Gα-binding and -activating (GBA) motif. We combine NMR spectroscopy, computational modelling and biochemistry to map changes in Gα caused by binding of GBA proteins with residue-level resolution...
May 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28513578/crystal-structure-of-a-multi-domain-human-smoothened-receptor-in-complex-with-a-super-stabilizing-ligand
#6
Xianjun Zhang, Fei Zhao, Yiran Wu, Jun Yang, Gye Won Han, Suwen Zhao, Andrii Ishchenko, Lintao Ye, Xi Lin, Kang Ding, Venkatasubramanian Dharmarajan, Patrick R Griffin, Cornelius Gati, Garrett Nelson, Mark S Hunter, Michael A Hanson, Vadim Cherezov, Raymond C Stevens, Wenfu Tan, Houchao Tao, Fei Xu
The Smoothened receptor (SMO) belongs to the Class Frizzled of the G protein-coupled receptor (GPCR) superfamily, constituting a key component of the Hedgehog signalling pathway. Here we report the crystal structure of the multi-domain human SMO, bound and stabilized by a designed tool ligand TC114, using an X-ray free-electron laser source at 2.9 Å. The structure reveals a precise arrangement of three distinct domains: a seven-transmembrane helices domain (TMD), a hinge domain (HD) and an intact extracellular cysteine-rich domain (CRD)...
May 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/28512295/camp-dependent-cell-differentiation-triggered-by-activated-crhr1-in-hippocampal-neuronal-cells
#7
Carolina Inda, Juan José Bonfiglio, Paula A Dos Santos Claro, Sergio A Senin, Natalia G Armando, Jan M Deussing, Susana Silberstein
Corticotropin-releasing hormone receptor 1 (CRHR1) activates the atypical soluble adenylyl cyclase (sAC) in addition to transmembrane adenylyl cyclases (tmACs). Both cAMP sources were shown to be required for the phosphorylation of ERK1/2 triggered by activated G protein coupled receptor (GPCR) CRHR1 in neuronal and neuroendocrine contexts. Here, we show that activated CRHR1 promotes growth arrest and neurite elongation in neuronal hippocampal cells (HT22-CRHR1 cells). By characterising CRHR1 signalling mechanisms involved in the neuritogenic effect, we demonstrate that neurite outgrowth in HT22-CRHR1 cells takes place by a sAC-dependent, ERK1/2-independent signalling cascade...
May 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28511989/biased-agonism-antagonism-at-the-angii-at1-receptor-implications-for-adrenal-aldosterone-production-and-cardiovascular-therapy
#8
REVIEW
Jennifer Maning, Shmuel Negussie, Michelle A Clark, Anastasios Lymperopoulos
Many of the effects of angiotensin II (AngII), including adrenocortical aldosterone release, are mediated by the AngII type 1 receptor (AT1R), a receptor with essential roles in cardiovascular homeostasis. AT1R belongs to the G protein-coupled receptor (GPCR) superfamily, mainly coupling to the Gq/11 type of G proteins. However, it also signals through βarrestins, oftentimes in parallel to eliciting G protein-dependent signaling. This has spurred infinite possibilities for cardiovascular pharmacology, since various beneficial effects are purportedly exerted by AT1R via βarrestins, unlike AT1R-induced G protein-mediated pathways that usually result in damaging cardiovascular effects, including hypertension and aldosterone elevation...
May 13, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28505258/modelling-and-mathematical-analysis-of-the-m-_-2-receptor-dependent-joint-signalling-and-secondary-messenger-network-in-cho-cells
#9
Benjamin Engelhardt, Janine Holze, Christina Elliott, George S Baillie, Maik Kschischo, Holger Fröhlich
The muscarinic M$_{2}$ receptor is a prominent member of the GPCR family and strongly involved in heart diseases. Recently published experimental work explored the cellular response to iperoxo-induced M$_{2}$ receptor stimulation in Chinese hamster ovary (CHO) cells. To better understand these responses, we modelled and analysed the muscarinic M$_{2}$ receptor-dependent signalling pathway combined with relevant secondary messenger molecules using mass action. In our literature-based joint signalling and secondary messenger model, all binding and phosphorylation events are explicitly taken into account in order to enable subsequent stoichiometric matrix analysis...
May 15, 2017: Mathematical Medicine and Biology: a Journal of the IMA
https://www.readbyqxmd.com/read/28502923/g-protein-coupled-receptor-signaling-through-gpr176-gz-and-rgs16-tunes-time-in-the-center-of-the-circadian-clock-review
#10
Kaoru Goto, Masao Doi, Tianyu Wang, Sumihiro Kunisue, Iori Murai, Hitoshi Okamura
G-protein-coupled receptors (GPCRs) constitute an immensely important class of drug targets with diverse clinical applications. There are still more than 120 orphan GPCRs whose cognate ligands and physiological functions are not known. A set of circadian pacemaker neurons that governs daily rhythms in behavior and physiology resides in the suprachiasmatic nucleus (SCN) in the brain. Malfunction of the circadian clock has been linked to a multitude of diseases, such as sleeping disorders, obesity, diabetes, cardiovascular diseases, and cancer, which makes the clock an attractive target for drug development...
May 13, 2017: Endocrine Journal
https://www.readbyqxmd.com/read/28502792/drug-binding-poses-relate-structure-with-efficacy-in-the-%C3%AE-opioid-receptor
#11
Katy J Sutcliffe, Graeme Henderson, Eamonn Kelly, Richard B Sessions
The μ-opioid receptor (MOPr) is a clinically important G protein-coupled receptor (GPCR) which couples to Gi/o proteins and arrestins. At present the receptor conformational changes that occur following agonist binding and activation are poorly understood. This study has employed molecular dynamics simulations to investigate the binding mode and receptor conformational changes induced by structurally similar opioid ligands of widely differing intrinsic agonist efficacy, norbuprenorphine, buprenorphine and diprenorphine...
May 11, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28499989/melanocortin-receptor-accessory-proteins-mraps-functions-in-the-melanocortin-system-and-beyond
#12
REVIEW
Alix A J Rouault, Dinesh K Srinivasan, Terry C Yin, Abigail A Lee, Julien A Sebag
G-protein coupled receptors (GPCRs) are regulated by numerous proteins including kinases, G-proteins, β-arrestins and accessory proteins. Several families of GPCR accessory proteins like Receptor Activity Modifying Proteins, Receptor Transporting Proteins and Melanocortin Receptor Accessory Proteins (MRAPs) have been identified as regulator of receptor trafficking, signaling and ligand specificity. The MRAP family contains two members, MRAP1 and MRAP2, responsible for the formation of a functional ACTH receptor and for the regulation of energy homeostasis respectively...
May 9, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28499341/positive-detection-of-gpcr-antagonists-using-a-system-for-inverted-expression-of-a-fluorescent-reporter-gene
#13
Nobuo Fukuda, Misato Kaishima, Jun Ishii, Shinya Honda
The yeast Saccharomyces cerevisiae is a useful eukaryotic host organism for studying GPCRs as monomolecular models. Fluorescent reporter gene assays for GPCRs provide a convenient assay for measuring receptor activity using fluorometric instruments. Generally, these assays detect receptor activation by agonistic ligands as the induction of fluorescent reporter expression, whereas antagonistic activities are detected by competition with agonistic ligands, resulting in decreases in fluorescence intensity. In the current study, we established a system for inverted expression of a fluorescent reporter by incorporating a PEST-tag and finding out a promoter inhibited by activation of the GPCR signaling pathway from yeast endogenous promoters...
May 12, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/28495999/%C3%AE-arrestin-mediated-regulation-of-the-human-ether-a-go-go-related-gene-herg-potassium-channel
#14
Matthew G Sangoi, Shawn M Lamothe, Jun Guo, Tonghua Yang, Wentao Li, Ellen G Avery, John T Fisher, Shetuan Zhang
The rapidly activating delayed rectifier K(+) channel (IKr) is encoded by the human ether-a-go-go-related gene (hERG), which is important for the repolarization of the cardiac action potential. Mutations in hERG or drugs can impair the function or decrease the expression level of hERG channels, leading to long QT syndrome (LQTS). Thus, it is important to understand hERG channel trafficking and its regulation. For this purpose, G protein-coupled receptors (GPCRs), which regulate a vast array of cellular processes, represent a useful route...
May 11, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28495495/translating-in-vitro-ligand-bias-into-in-vivo-efficacy
#15
REVIEW
Louis M Luttrell, Stuart Maudsley, Diane Gesty-Palmer
It is increasingly apparent that ligand structure influences both the efficiency with which G protein-coupled receptors (GPCRs) engage their downstream effectors and the manner in which they are activated. Thus, 'biased' agonists, synthetic ligands whose intrinsic efficacy differs from the native ligand, afford a strategy for manipulating GPCR signaling in ways that promote beneficial signals while blocking potentially deleterious ones. Still, there are significant challenges in relating in vitro ligand efficacy, which is typically measured in heterologous expression systems, to the biological response in vivo, where the ligand is acting on natively expressed receptors and in the presence of the endogenous ligand...
May 7, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28493967/water-permeation-through-the-internal-water-pathway-in-activated-gpcr-rhodopsin
#16
Katsufumi Tomobe, Eiji Yamamoto, Kholmirzo Kholmurodov, Kenji Yasuoka
Rhodopsin is a light-driven G-protein-coupled receptor that mediates signal transduction in eyes. Internal water molecules mediate activation of the receptor in a rhodopsin cascade reaction and contribute to conformational stability of the receptor. However, it remains unclear how internal water molecules exchange between the bulk and protein inside, in particular through a putative solvent pore on the cytoplasmic. Using all-atom molecular dynamics simulations, we identified the solvent pore on cytoplasmic side in both the Meta II state and the Opsin...
2017: PloS One
https://www.readbyqxmd.com/read/28487995/c-terminus-of-ox2r-significantly-affects-downstream-signaling-pathways
#17
Chunmei Wang, Chao Xu, Minghui Liu, Yanyou Pan, Bo Bai, Jing Chen
The human orexin 2 receptor (OX2R) is a G-protein‑coupled receptor (GPCR) that has been implicated in a number of diverse physiological functions. Recent studies have identified a number of functions of the C‑termini of GPCRs. However, the importance of the OX2R C‑terminus in regulating signaling and surface expression remains unclear. In the present study, the function of the OX2R C‑terminus was investigated using three C‑terminal mutants, which were truncated at residues 368, 384 and 414, respectively, and the wild‑type control, which expressed the full‑length OX2R...
May 9, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28484645/gene-expression-profiling-of-the-optic-nerve-head-of-patients-with-primary-open-angle-glaucoma
#18
Xinrong Wang, Ke Gong, Haiyan Li, Congyi Wang, Chaoyi Qu, Hui Li
Background. The pressure-induced axonal injury of the vulnerable ONH has led many researchers to view glaucoma from the perspective of the genetic basis of the angle of the ONH. However, genetic studies on POAG from this perspective are limited. Methods. Microarray dataset GSE45570 of the ONH of healthy individuals and POAG patients were downloaded from the Gene Expression Omnibus. After screening for the DEGs using the limma package, enrichment analysis was performed using DAVID. The DEG interaction network was constructed using cancer spider at BioProfiling...
2017: Journal of Ophthalmology
https://www.readbyqxmd.com/read/28482214/active-state-structures-of-g-protein-coupled-receptors-highlight-the-similarities-and-differences-in-the-g-protein-and-arrestin-coupling-interfaces
#19
REVIEW
Byron Carpenter, Christopher G Tate
G protein-coupled receptors (GPCRs) regulate cellular signalling through heterotrimeric G proteins and arrestins in response to an array of extracellular stimuli. Structure determination of GPCRs in an active conformation bound to intracellular signalling proteins has proved to be highly challenging. Nonetheless, three new structures of GPCRs in an active state have been published during the last year, namely the adenosine A2A receptor (A2AR) bound to an engineered G protein, opsin bound to visual arrestin and the μ opioid receptor (μOR) bound to a G protein-mimicking nanobody...
May 5, 2017: Current Opinion in Structural Biology
https://www.readbyqxmd.com/read/28480316/expression-and-purification-of-mini-g-proteins-from-escherichia-coli
#20
Byron Carpenter, Christopher G Tate
Heterotrimeric G proteins modulate intracellular signalling by transducing information from cell surface G protein-coupled receptors (GPCRs) to cytoplasmic effector proteins. Structural and functional characterisation of GPCR-G protein complexes is important to fully decipher the mechanism of signal transduction. However, native G proteins are unstable and conformationally dynamic when coupled to a receptor. We therefore developed an engineered minimal G protein, mini-Gs, which formed a stable complex with GPCRs, and facilitated the crystallisation and structure determination of the human adenosine A2A receptor (A2AR) in its active conformation...
April 20, 2017: Bio-protocol
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