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https://www.readbyqxmd.com/read/29240722/g-protein-coupled-receptors-at-the-crossroad-between-physiologic-and-pathologic-angiogenesis-old-paradigms-and-emerging-concepts
#1
REVIEW
Ernestina M De Francesco, Federica Sotgia, Robert B Clarke, Michael P Lisanti, Marcello Maggiolini
G protein-coupled receptors (GPCRs) have been implicated in transmitting signals across the extra- and intra-cellular compartments, thus allowing environmental stimuli to elicit critical biological responses. As GPCRs can be activated by an extensive range of factors including hormones, neurotransmitters, phospholipids and other stimuli, their involvement in a plethora of physiological functions is not surprising. Aberrant GPCR signaling has been regarded as a major contributor to diverse pathologic conditions, such as inflammatory, cardiovascular and neoplastic diseases...
December 14, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29239726/camp-signaling-regulates-dna-hydroxymethylation-by-augmenting-the-intracellular-labile-ferrous-iron-pool
#2
Vladimir Camarena, David W Sant, Tyler C Huff, Sushimita Mustafi, Ryan K Muir, Allegra T Aron, Christopher J Chang, Adam R Renslo, Paula Monje, Gaofeng Wang
It is widely accepted that cAMP regulates gene transcription principally by activating the protein kinase A (PKA)-targeted transcription factors. Here, we show that cAMP enhances the generation of 5-hydroxymethylcytosine (5hmC) in multiple cell types. 5hmC is converted from 5-methylcytosine (5mC) by Tet methylcytosine dioxygenases, for which Fe(II) is an essential cofactor. The promotion of 5hmC was mediated by a prompt increase of the intracellular labile Fe(II) pool (LIP). cAMP enhanced the acidification of endosomes for Fe(II) release to the LIP likely through RapGEF2...
December 14, 2017: ELife
https://www.readbyqxmd.com/read/29233848/g-protein-coupled-receptors-targeting-insulin-resistance-obesity-and-type-2-diabetes-mellitus
#3
REVIEW
Darren M Riddy, Philippe Delerive, Roger J Summers, Patrick M Sexton, Christopher J Langmead
G protein-coupled receptors (GPCRs) continue to be important discovery targets for the treatment of type 2 diabetes mellitus (T2DM). Many GPCRs are directly involved in the development of insulin resistance and β-cell dysfunction, and in the etiology of inflammation that can lead to obesity-induced T2DM. This review summarizes the current literature describing a number of well-validated GPCR targets, but also outlines several new and promising targets for drug discovery. We highlight the importance of understanding the role of these receptors in the disease pathology, and their basic pharmacology, which will pave the way to the development of novel pharmacological probes that will enable these targets to fulfill their promise for the treatment of these metabolic disorders...
January 2018: Pharmacological Reviews
https://www.readbyqxmd.com/read/29233753/targeting-the-26s-proteasome-to-protect-against-proteotoxic-diseases
#4
REVIEW
Natura Myeku, Karen E Duff
Aggregates of misfolded proteins can compromise the function of the 26S proteasome complex, leaving neurons susceptible to accelerated and impaired protein homeostasis, thereby contributing to the pathogenesis of neurodegeneration. Strategies aimed at enhancing the function of the 26S proteasome via phosphorylation of key subunit epitopes have been effective in reducing protein aggregates in mouse models of disease. We discuss how phosphodiesterase (PDE) inhibitors and G protein-coupled receptor (GPCR)-targeted drugs might be considered as candidate therapeutics, acting on second messenger signal transduction...
December 9, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/29231251/mechanoactivation-of-the-angiotensin-ii-type-1-receptor-induces-%C3%AE-arrestin-biased-signaling-through-g%C3%AE-i-coupling
#5
Jialu Wang, Kenji Hanada, Clarice Gareri, Howard A Rockman
Ligand activation of the angiotensin II type 1 receptor (AT1R), a member of the G protein-coupled receptor (GPCR) family, stimulates intracellular signaling to mediate a variety of physiological responses. The AT1R is also known to be a mechanical sensor. When activated by mechanical stretch, the AT1R can signal via the multifunctional adaptor protein β-arrestin, rather than through classical heterotrimeric G protein pathways. To date, the AT1R conformation induced by membrane stretch in the absence of ligand was thought to be the same as that induced by β-arrestin-biased agonists, which selectively engage β-arrestin thereby preventing G protein coupling...
December 12, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29227550/live-cell-visualization-of-calcium-flux-in-vibratome-cut-thick-sections-of-viable-tumor-tissue
#6
James Koh, Joyce A Hogue, Julie A Sosa
This unit outlines a live-cell imaging approach developed for visualization of intracellular calcium flux in human parathyroid tumors following stimulation of the calcium-sensing receptor (CASR), a class C G protein-coupled receptor (GPCR). The primary assay readout, intracellular calcium release induced by activation of the inositol triphosphate receptor, is potentially generalizable to multiple other GPCR signaling events that utilize this common downstream signal transduction pathway. Advantages of the approach include: (1) preservation of native tissue context and positional information, allowing direct visualization of intratumoral functional heterogeneity; (2) quantitative documentation of reactivity to a physiological stimulus in an experimentally tractable ex vivo system; and (3) generation of a dynamic, functional classifier of tumor biochemical behavior to augment static marker assessment...
December 11, 2017: Current Protocols in Cell Biology
https://www.readbyqxmd.com/read/29227473/structure-inspired-design-of-%C3%AE-arrestin-biased-ligands-for-aminergic-gpcrs
#7
John D McCorvy, Kyle V Butler, Brendan Kelly, Katie Rechsteiner, Joel Karpiak, Robin M Betz, Bethany L Kormos, Brian K Shoichet, Ron O Dror, Jian Jin, Bryan L Roth
Development of biased ligands targeting G protein-coupled receptors (GPCRs) is a promising approach for current drug discovery. Although structure-based drug design of biased agonists remains challenging even with an abundance of GPCR crystal structures, we present an approach for translating GPCR structural data into β-arrestin-biased ligands for aminergic GPCRs. We identified specific amino acid-ligand contacts at transmembrane helix 5 (TM5) and extracellular loop 2 (EL2) responsible for Gi/o and β-arrestin signaling, respectively, and targeted those residues to develop biased ligands...
December 11, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/29222765/cancer-driver-g-protein-coupled-receptor-gpcr-induced-%C3%AE-catenin-nuclear-localization-the-transcriptional-junction
#8
REVIEW
Jeetendra Kumar Nag, Tatyana Rudina, Myriam Maoz, Sorina Grisaru-Granovsky, Beatrice Uzieky, Rachel Bar-Shavit
G protein-coupled receptors (GPCRs) comprise the main signal-transmitting components in the cell membrane. Over the past several years, biochemical and structural analyses have immensely enhanced our knowledge of GPCR involvement in health and disease states. The present review focuses on GPCRs that are cancer drivers, involved in tumor growth and development. Our aim is to highlight the involvement of stabilized β-catenin molecular machinery with a specific array of GPCRs. We discuss recent advances in understanding the molecular path leading to β-catenin nuclear localization and transcriptional activity and their implications for future cancer therapy research...
December 8, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/29212811/altered-expression-of-hepatic-%C3%AE-adrenergic-receptors-in-aging-rats-implications-for-age-related-metabolic-dysfunction-in-liver
#9
Yun Shi, Zhen-Ju Shu, Hanzhou Wang, Jeffrey L Barnes, Chih-Ko Yeh, Paramita M Ghosh, Michael S Katz, Amrita Kamat
Increased β-adrenergic receptor (β-AR)-mediated activation of adenylyl cyclase (AC) in rat liver during aging has been linked to age-related increases in hepatic glucose output and hepatosteatosis. In this study we investigated the expression of β-ARs, individual receptor subtypes, and G protein-coupled receptor (GPCR) regulatory proteins in livers from aging rats. Radioligand binding studies demonstrated that β-AR density increased by >3-fold in hepatocyte membranes from senescent (24 mo old) compared to young adult (7 mo old) rats, and that this phenomenon was blocked by food restriction which is known to retard aging processes in rodents...
December 6, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/29212031/integration-of-gpcr-signaling-and-sorting-from-very-early-endosomes-via-opposing-appl1-mechanisms
#10
Silvia Sposini, Frederic G Jean-Alphonse, Mohammed A Ayoub, Affiong Oqua, Camilla West, Stuart Lavery, Jan J Brosens, Eric Reiter, Aylin C Hanyaloglu
Endocytic trafficking is a critical mechanism for cells to decode complex signaling pathways, including those activated by G-protein-coupled receptors (GPCRs). Heterogeneity in the endosomal network enables GPCR activity to be spatially restricted between early endosomes (EEs) and the recently discovered endosomal compartment, the very early endosome (VEE). However, the molecular machinery driving GPCR activity from the VEE is unknown. Using luteinizing hormone receptor (LHR) as a prototype GPCR for this compartment, along with additional VEE-localized GPCRs, we identify a role for the adaptor protein APPL1 in rapid recycling and endosomal cAMP signaling without impacting the EE-localized β2-adrenergic receptor...
December 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/29211777/alpha-conotoxin-buia-globular-isomer-is-a-competitive-antagonist-for-oleoyl-l-alpha-lysophosphatidic-acid-binding-to-lpar6-a-molecular-dynamics-study
#11
Saima Younis, Sajid Rashid
Lysophosphatidic acid receptor 6 (LPAR6) is a G-protein coupled receptor (GPCR) involved in hair development and cytoskeleton formation in mammals. Its proliferation is implicated in several forms of cancer including liver cancer, squamous cell carcinoma and metastatic prostate cancer. Current study emphasizes the isolation of competitive non-lipid and stable peptide antagonists for Lysophosphatidic acid ligand. A total of 148 conotoxin structures were characterized for their binding abilities against LPAR6...
2017: PloS One
https://www.readbyqxmd.com/read/29209334/absence-of-the-non-signalling-chemerin-receptor-ccrl2-exacerbates-acute-inflammatory-responses-in-vivo
#12
Daniel Regan-Komito, Sophia Valaris, Theodore S Kapellos, Carlota Recio, Lewis Taylor, David R Greaves, Asif J Iqbal
Chemerin is a chemotactic protein that induces migration of several immune cells including macrophages, immature dendritic cells, and NK cells. Chemerin binds to three G protein-coupled receptors (GPCRs), including CCRL2. The exact function of CCRL2 remains unclear. CCRL2 expression is rapidly upregulated during inflammation, but it lacks the intracellular DRYLAIV motif required for classical GPCR downstream signalling pathways, and it has not been reported to internalise chemerin upon binding. The aim of this study was to investigate what role if any CCRL2 plays during acute inflammation...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29209002/the-orientation-and-stability-of-the-gpcr-arrestin-complex-in-a-lipid-bilayer
#13
Dali Wang, Hua Yu, Xiangdong Liu, Jianqiang Liu, Chen Song
G protein-coupled receptors (GPCRs) constitute a large family of membrane proteins that plays a key role in transmembrane signal transduction and draw wide attention since it was discovered. Arrestin is a small family of proteins which can bind to GPCRs, block G protein interactions and redirect signaling to G-protein-independent pathways. The detailed mechanism of how arrestin interacts with GPCR remains elusive. Here, we conducted molecular dynamics simulations with coarse-grained (CG) and all-atom (AA) models to study the complex structure formed by arrestin and rhodopsin, a prototypical GPCR, in a POPC bilayer...
December 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29208743/latency-associated-expression-of-human-cytomegalovirus-us28-attenuates-cell-signaling-pathways-to-maintain-latent-infection
#14
Benjamin A Krishna, Emma L Poole, Sarah E Jackson, Martine J Smit, Mark R Wills, John H Sinclair
Reactivation of human cytomegalovirus (HCMV) latent infection from early myeloid lineage cells constitutes a threat to immunocompromised or immune-suppressed individuals. Consequently, understanding the control of latency and reactivation to allow targeting and killing of latently infected cells could have far-reaching clinical benefits. US28 is one of the few viral genes that is expressed during latency and encodes a cell surface G protein-coupled receptor (GPCR), which, during lytic infection, is a constitutive cell-signaling activator...
December 5, 2017: MBio
https://www.readbyqxmd.com/read/29204712/presynaptic-ethanol-actions-potential-roles-in-ethanol-seeking
#15
David M Lovinger
Ethanol produces intoxication through actions on numerous molecular and cellular targets. Adaptations involving these and other targets contribute to chronic drug actions that underlie continued and problematic drinking. Among the mechanisms involved in these ethanol actions are alterations in presynaptic mechanisms of synaptic transmission, including presynaptic protein function and excitation-secretion coupling. At synapses in the central nervous system (CNS), excitation-secretion coupling involves ion channel activation followed by vesicle fusion and neurotransmitter release...
December 5, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/29203889/single-molecule-imaging-reveals-dimerization-oligomerization-of-cxcr4-on-plasma-membrane-closely-related-to-its-function
#16
Baosheng Ge, Jun Lao, Jiqiang Li, Yao Chen, Yanzhuo Song, Fang Huang
Dimerization and oligomerization of G-protein coupled receptors (GPCRs) have emerged as important characters during their trans-membrane signal transduction. However, until now the relationship between GPCR dimerization and their trans-membrane signal transduction function is still uncovered. Here, using pertussis toxin (PTX) to decouple the receptor from G protein complex and with single-molecule imaging, we show that in the presence of agonist, cells treated with PTX showed a decrease in the number of dimers and oligomers on the cell surface compared with untreated ones, which suggests that oligomeric status of CXCR4 could be significantly influenced by the decoupling of G protein complex during its signal transduction process...
December 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29203139/structural-mapping-of-adenosine-receptor-mutations-ligand-binding-and-signaling-mechanisms
#17
REVIEW
Willem Jespers, Anke C Schiedel, Laura H Heitman, Robert M Cooke, Lisa Kleene, Gerard J P van Westen, David E Gloriam, Christa E Müller, Eddy Sotelo, Hugo Gutiérrez-de-Terán
The four adenosine receptors (ARs), A1, A2A, A2B, and A3, constitute a subfamily of G protein-coupled receptors (GPCRs) with exceptional foundations for structure-based ligand design. The vast amount of mutagenesis data, accumulated in the literature since the 1990s, has been recently supplemented with structural information, currently consisting of several inactive and active structures of the A2A and inactive conformations of the A1 ARs. We provide the first integrated view of the pharmacological, biochemical, and structural data available for this receptor family, by mapping onto the relevant crystal structures all site-directed mutagenesis data, curated and deposited at the GPCR database (available through http://www...
December 1, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/29198881/role-of-arsenic-exposure-in-adipose-tissue-dysfunction-and-its-possible-implication-in-diabetes-pathophysiology
#18
REVIEW
Kaviyarasi Renu, Harishkumar Madhyastha, Radha Madhyastha, Masugi Maruyama, Sankarganesh Arunachlam, Abilash V G
Exposure to arsenic in drinking water can stimulate a diverse number of diseases that originate from impaired lipid metabolism in adipose and glucose metabolism, leading to insulin resistance. Arsenic inhibits differentiation of adipocyte and mediates insulin resistance with diminutive information on arsenicosis on lipid storage and lipolysis. This review focused on different mechanisms and pathways involved in adipogenesis and lipolysis in adipose tissue during arsenic-induced diabetes. Though arsenic is known to cause type2 diabetes through different mechanisms, the role of adipose tissue in causing type2 diabetes is still unclear...
November 30, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/29198647/isolation-functional-characterization-of-allatotropin-receptor-from-the-cotton-bollworm-helicoverpa-armigera
#19
Fang Zhang, Jun Wang, Kiran Thakur, Fei Hu, Jian-Guo Zhang, Xing-Fu Jiang, Shi-Hen An, Hongbo Jiang, Li Jiang, Zhao-Jun Wei
Insect allatotropin (AT) plays multi-functions including regulation of juvenile hormone synthesis, growth, development and reproduction. In the present study, the full-length cDNA encoding the AT receptor was cloned from the brain of Helicoverpa armigera (Helar-ATR). The ORF of Helar-ATR exhibited the characteristic seven transmembrane domains of the G protein-coupled receptor (GPCR) and was close to the ATR of Manduca sexta in the phylogenetic tree. The Helar-ATR expressed in vertebrate cell lines can be activated by Helar-AT and each Helar-ATL in a dose-responsive manner, in the following order: Helar-ATLI>Helar-ATLII>Helar-AT>Helar-ATLIII...
November 30, 2017: Peptides
https://www.readbyqxmd.com/read/29196502/identifying-the-localization-and-exploring-a-functional-role-for-gprc5c-in-the-kidney
#20
Premraj Rajkumar, Boyoung Cha, Jianyi Yin, Lois J Arend, Teodor G Păunescu, Yoshio Hirabayashi, Mark Donowitz, Jennifer L Pluznick
The investigation of orphan GPCRs (GPRs) has the potential to uncover novel insights into whole animal physiology. In this study, our goal was to determine the renal localization of Gprc5c, a receptor that we previously reported to be highly expressed in murine whole kidney, and to examine physiologic parameters in Gprc5c knockout (KO) mice to gain insight into function. Gprc5c localized to the apical membrane of renal proximal tubules (PTs) in mice, rats, and humans. With the comparison of Gprc5c wild-type (WT) and KO mice, we found that Gprc5c KO mice have altered acid-base homeostasis...
December 1, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
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