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https://www.readbyqxmd.com/read/28921001/c3ar-and-c5ar1-act-as-key-regulators-of-human-and-mouse-%C3%AE-cell-function
#1
Patricio Atanes, Inmaculada Ruz-Maldonado, Attilio Pingitore, Ross Hawkes, Bo Liu, Min Zhao, Guo Cai Huang, Shanta J Persaud, Stefan Amisten
AIMS: Complement components 3 and 5 (C3 and C5) play essential roles in the complement system, generating C3a and C5a peptides that are best known as chemotactic and inflammatory factors. In this study we characterised islet expression of C3 and C5 complement components, and the impact of C3aR and C5aR1 activation on islet function and viability. MATERIALS AND METHODS: Human and mouse islet mRNAs encoding key elements of the complement system were quantified by qPCR and distribution of C3 and C5 proteins was determined by immunohistochemistry...
September 18, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28912160/dopamine-d2-receptors-modulate-pyramidal-neurons-in-mouse-medial-prefrontal-cortex-through-a-stimulatory-g-protein-pathway
#2
Sarah E Robinson, Vikaas S Sohal
Dopaminergic modulation of prefrontal cortex is believed to play key roles in many cognitive functions and to be disrupted in pathological conditions such as schizophrenia. We have previously described a phenomenon whereby dopamine D2 receptor (D2R) activation elicits afterdepolarizations (ADPs) in subcortically-projecting (SC) pyramidal neurons within L5 of the prefrontal cortex. These D2R-induced ADPs only occur following synaptic input which activates NMDA receptors (NMDARs) even when the delay between the synaptic input and afterdepolarizations is relatively long, e...
September 14, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28900175/dynamic-and-kinetic-elements-of-%C3%A2%C2%B5-opioid-receptor-functional-selectivity
#3
Abhijeet Kapoor, Gerard Martinez-Rosell, Davide Provasi, Gianni de Fabritiis, Marta Filizola
While the therapeutic effect of opioids analgesics is mainly attributed to µ-opioid receptor (MOR) activation leading to G protein signaling, their side effects have mostly been linked to β-arrestin signaling. To shed light on the dynamic and kinetic elements underlying MOR functional selectivity, we carried out close to half millisecond high-throughput molecular dynamics simulations of MOR bound to a classical opioid drug (morphine) or a potent G protein-biased agonist (TRV-130). Statistical analyses of Markov state models built using this large simulation dataset combined with information theory enabled, for the first time: a) Identification of four distinct metastable regions along the activation pathway, b) Kinetic evidence of a different dynamic behavior of the receptor bound to a classical or G protein-biased opioid agonist, c) Identification of kinetically distinct conformational states to be used for the rational design of functionally selective ligands that may eventually be developed into improved drugs; d) Characterization of multiple activation/deactivation pathways of MOR, and e) Suggestion from calculated transition timescales that MOR conformational changes are not the rate-limiting step in receptor activation...
September 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28898928/importance-of-the-second-extracellular-loop-for-melatonin-mt1-receptor-function-and-absence-of-melatonin-binding-in-gpr50
#4
Nathalie Clement, Nicolas Renault, Jean-Luc Guillaume, Erika Cecon, Anne-Sophie Journé, Xavier Laurent, Kenjiro Tadagaki, Francis Cogé, Arnaud Gohier, Philippe Delagrange, Philippe Chavatte, Ralf Jockers
BACKGROUND AND PURPOSE: Recent crystal structures of G protein-coupled receptors (GPCRs) highlight the previously unappreciated role of the 2(nd) extracellular (E2) loop in ligand binding and gating and receptor activation. Here we studied the role of the E2 loop in the activation of the melatonin MT1 receptor (MT1 ) and in the inactivation of the closely related orphan GPR50 receptor. EXPERIMENTAL APPROACH: Chimeric MT1 -GPR50 receptors were generated and analyzed for 2-[(125) I]iodomelatonin binding, Gi /cAMP signaling and β-arrestin 2 recruitment assisted by computational molecular dynamics (MD) simulations...
September 12, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28893976/teaching-an-old-drug-new-tricks-agonism-antagonism-and-biased-signaling-of-pilocarpine-through-m3-muscarinic-acetylcholine-receptor
#5
Alexey Pronin, Qiang Wang, Vladlen Z Slepak
Pilocarpine is a prototypical drug used to treat glaucoma and dry mouth and classified as either a full or partial muscarinic agonist. Here, we report several unexpected results pertaining to its interaction with muscarinic M3 receptor (M3R). We found that pilocarpine was 1,000 times less potent in stimulating mouse eye pupil constriction than muscarinic agonists oxotremorin-M (Oxo-M) or carbachol (CCh), even though all three ligands have similar Kd values for M3R. In contrast to CCh or Oxo-M, pilocarpine does not induce Ca2+ mobilization via endogenous M3R in HEK293T or mouse insulinoma MIN6 cells...
September 11, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28893975/agonist-dependent-and-independent-kappa-opioid-receptor-phosphorylation-showed-distinct-phosphorylation-patterns-and-resulted-in-different-cellular-outcomes
#6
Yi-Ting Chiu, Chongguang Chen, Daohai Yu, Stefan Schulz, Lee-Yuan Liu-Chen
We reported previously that the selective agonist U50,488H promoted phosphorylation of the mouse kappa opioid receptor (KOPR) at residues S356, T357, T363 and S369. Here, we found that agonist (U50,488H)-dependent KOPR phosphorylation at all the residues were mediated by Gi/oα proteins and multiple protein kinases [GRKs2, 3, 5 and 6 and protein kinase C (PKC)]. In addition, PKC activation by phorbol ester induced agonist-independent KOPR phosphorylation. Compared with U50,488H, PKC activation promoted much higher S356/T357 phosphorylation, much lower T363 phosphorylation and similar levels of S369 phosphorylation...
September 11, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28891236/a-disease-associated-mutation-in-the-adhesion-gpcr-bai2-adgrb2-increases-receptor-signaling-activity
#7
Ryan H Purcell, Camilo Toro, William A Gahl, Randy A Hall
Mutations in G protein-coupled receptors (GPCRs) that increase constitutive signaling activity can cause human disease. A de novo C-terminal mutation (R1465W) in the adhesion GPCR BAI2 (also known as ADGRB2) was identified in a patient suffering from progressive spastic paraparesis and other neurological symptoms. In vitro studies revealed that this mutation strongly increases the constitutive signaling activity of an N-terminally cleaved form of BAI2, which represents the activated form of the receptor. Further studies dissecting the mechanism(s) underling this effect revealed that wild-type BAI2 primarily couples to Gαz , with the R1465W mutation conferring increased coupling to Gαi ...
September 10, 2017: Human Mutation
https://www.readbyqxmd.com/read/28888989/noradrenaline-oxymetazoline-and-phorbol-myristate-acetate-induce-distinct-functional-actions-and-phosphorylation-patterns-of-%C3%AE-1a-adrenergic-receptors
#8
Rocío Alcántara-Hernández, Aurelio Hernández-Méndez, M Teresa Romero-Ávila, Marco A Alfonzo-Méndez, André S Pupo, J Adolfo García-Sáinz
In LNCaP cells that stably express α1A-adrenergic receptors, oxymetazoline increased intracellular calcium and receptor phosphorylation, however, this agonist was a weak partial agonist, as compared to noradrenaline, for calcium signaling. Interestingly, oxymetazoline-induced receptor internalization and desensitization displayed greater effects than those induced by noradrenaline. Phorbol myristate acetate induced modest receptor internalization and minimal desensitization. α1A-Adrenergic receptor interaction with β-arrestins (colocalization/coimmunoprecipitation) was induced by noradrenaline and oxymetazoline and, to a lesser extent, by phorbol myristate acetate...
September 6, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28888936/%C3%AE-arrestin-2-is-involved-in-irisin-induced-glucose-metabolism-in-type-2-diabetes-via-p38-mapk-signaling
#9
Yaling Pang, Haihui Zhu, Jianqin Xu, Lihua Yang, Lingjiao Liu, Jing Li
Type 2 diabetes mellitus (T2DM) is a common metabolic disease worldwide. It has been reported that irisin play regulatory role in glucose metabolism in T2DM. However, the underlying mechanism involved in that is not completely known. Herein, we determined the novel role of β-arrestin-2 in irisin-induced glucose utilization in diabetes. Effects of irisin and β-arrestin-2 on glucose utilization were investigated in a rat model of diabetes and in diabetic C2C12 cells in vitro. Results showed that irisin had positive role in glucose metabolism via regulating glucose tolerance as well as uptake in cardiac and skeletal muscle tissues, as evidenced by IPGTT, 2-deoxyglucose uptake and plasma membrane GLUT-4 assay...
September 6, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28883043/ffar2-ffar3-receptor-heteromerization-modulates-short-chain-fatty-acid-sensing
#10
Zhiwei Ang, Ding Xiong, Min Wu, Jeak Ling Ding
Free fatty acid receptors (FFAR2/FFA2/GPR43 and FFAR3/FFA3/GPR41) are mammalian receptors for gut microbiota-derived short-chain fatty acids (SCFAs). These receptors are promising drug targets for obesity, colitis, colon cancer, asthma, and arthritis. Here, we demonstrate that FFAR2 and FFAR3 interact to form a heteromer in primary human monocytes and macrophages via proximity ligation assay, and during heterologous expression in HEK293 cells via bimolecular fluorescence complementation and fluorescence resonance energy transfer...
September 7, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28881784/selective-inhibitors-of-nuclear-export-sine-compounds-block-proliferation-and-migration-of-triple-negative-breast-cancer-cells-by-restoring-expression-of-arrdc3
#11
Young Hwa Soung, Trinayan Kashyap, Thalia Nguyen, Garima Yadav, Hua Chang, Yosef Landesman, Jun Chung
Arrestin-related domain-containing protein-3 (ARRDC3) is one of 6 mammalian arrestins, which suppresses metastasis by inducing degradation of phosphorylated β2-adrenergic receptor (β2 AR) and integrin β4 (ITG β4). Our previous studies demonstrated that expression of ARRDC3 is epigentically silenced in Triple Negative Breast Cancer (TNBC) cells, and the forced expression of ARRDC3 significantly reduced the invasive potential of TNBC cells. In the current study, we found that Selective Inhibitors of Nuclear Export (SINE) compounds (KPT-185 and selinexor (KPT-330)) restore ARRDC3 expression in TNBC cell lines (MDA-MB-231 and MDA-MB-468) at both the mRNA and protein level in a dose and time course dependent manner...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28880373/supernatants-and-lipids-from-stored-red-blood-cells-activate-pulmonary-microvascular-endothelium-through-the-blt2-receptor-and-protein-kinase-c-activation
#12
Christopher C Silliman, Marguerite R Kelher, Samina Y Khan, F Bernadette West, Nathan J D McLaughlin, David J Elzi, Kelly England, Jason Bjornsen, Susan A Kuldanek, Anirban Banerjee
BACKGROUND: Although transfusion is a lifesaving intervention, it may be associated with significant morbidity in injured patients. We hypothesize that stored red blood cells (RBCs) induce proinflammatory activation of human pulmonary microvascular endothelial cells (HMVECs) resulting in neutrophil (PMN) adhesion and predisposition to acute lung injury (ALI). STUDY DESIGN AND METHODS: Ten units of RBCs were collected; 50% (by weight) were leukoreduced (LR-RBCs) and the remainder was unmodified and stored in additive solution-5 (AS-5)...
September 6, 2017: Transfusion
https://www.readbyqxmd.com/read/28877982/non-canonical-regulation-of-insulin-mediated-erk-activation-by-phosphoinositide-3-kinase-%C3%AE
#13
Maradumane L Mohan, Arunachal Chatterjee, Swetha Ganapathy, Sromona Mukherjee, Sowmya Srikanthan, George P Jolly, Rohit S Anand, Sathyamangla V Naga Prasad
Classically Class IB Phosphoinositide 3-kinase (PI3Kγ) plays a role in ERK activation following G-protein coupled receptor (GPCR) activation. Knock-down of PI3Kγ unsuspectingly resulted in loss of ERK activation to receptor tyrosine kinase-agonists like epidermal growth factor or insulin. Mouse embryonic fibroblasts (MEFs) or primary adult cardiac fibroblasts isolated from PI3Kγ knock-out mice (PI3KγKO) showed loss in insulin-stimulated ERK activation. However, expression of kinase-dead PI3Kγ resulted in rescue of insulin-stimulated ERK activation...
September 6, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28874589/dual-role-of-mitochondria-in-producing-melatonin-and-driving-gpcr-signaling-to-block-cytochrome-c-release
#14
Yalikun Suofu, Wei Li, Frédéric G Jean-Alphonse, Jiaoying Jia, Nicolas K Khattar, Jiatong Li, Sergei V Baranov, Daniela Leronni, Amanda C Mihalik, Yanqing He, Erika Cecon, Vanessa L Wehbi, JinHo Kim, Brianna E Heath, Oxana V Baranova, Xiaomin Wang, Matthew J Gable, Eric S Kretz, Giulietta Di Benedetto, Timothy R Lezon, Lisa M Ferrando, Timothy M Larkin, Mara Sullivan, Svitlana Yablonska, Jingjing Wang, M Beth Minnigh, Gérald Guillaumet, Franck Suzenet, R Mark Richardson, Samuel M Poloyac, Donna B Stolz, Ralf Jockers, Paula A Witt-Enderby, Diane L Carlisle, Jean-Pierre Vilardaga, Robert M Friedlander
G protein-coupled receptors (GPCRs) are classically characterized as cell-surface receptors transmitting extracellular signals into cells. Here we show that central components of a GPCR signaling system comprised of the melatonin type 1 receptor (MT1), its associated G protein, and β-arrestins are on and within neuronal mitochondria. We discovered that the ligand melatonin is exclusively synthesized in the mitochondrial matrix and released by the organelle activating the mitochondrial MT1 signal-transduction pathway inhibiting stress-mediated cytochrome c release and caspase activation...
September 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28874463/is-%C3%AE-arrestin-2-a-magic-bullet-for-heart-failure-treatment
#15
EDITORIAL
Pavel Zhabyeyev, Hao Zhang, Gavin Y Oudit
No abstract text is available yet for this article.
September 5, 2017: Hypertension
https://www.readbyqxmd.com/read/28874462/%C3%AE-arrestin2-improves-post-myocardial-infarction-heart-failure-via-sarco-endo-plasmic-reticulum-ca-2-atpase-dependent-positive-inotropy-in-cardiomyocytes
#16
Katie A McCrink, Jennifer Maning, Angela Vu, Malika Jafferjee, Christine Marrero, Ava Brill, Ashley Bathgate-Siryk, Samalia Dabul, Walter J Koch, Anastasios Lymperopoulos
Heart failure is the leading cause of death in the Western world, and new and innovative treatments are needed. The GPCR (G protein-coupled receptor) adapter proteins βarr (β-arrestin)-1 and βarr-2 are functionally distinct in the heart. βarr1 is cardiotoxic, decreasing contractility by opposing β1AR (adrenergic receptor) signaling and promoting apoptosis/inflammation post-myocardial infarction (MI). Conversely, βarr2 inhibits apoptosis/inflammation post-MI but its effects on cardiac function are not well understood...
September 5, 2017: Hypertension
https://www.readbyqxmd.com/read/28870802/%C3%AE-arrestin-biased-dopamine-d2-receptor-partial-agonists-synthesis-and-pharmacological-evaluation
#17
Barbara Männel, Harald Hübner, Dorothée Möller, Peter Gmeiner
β-Arrestin biased G protein-coupled receptor ligands represent important molecular probes and may increase favorable drug action and safety as novel therapeutics. Starting from recently discovered hydroxy-substituted heterocyclic piperazine scaffolds, we have developed a series of dopamine D2 receptor ligands with a pyrazolo[1,5-a]pyridine as secondary pharmacophore that is functionalized in position 3 by a formyl or hydroxyiminomethyl substituent. The ligands, especially the benzoxazinone 9d, were found to stimulate substantial β-arrestin-2 recruitment, while being nearly devoid of activity in a GTPγS binding assay...
August 24, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28869270/proteomic-and-genetic-analysis-of-the-response-of-s-cerevisiae-to-soluble-copper-leads-to-improvement-of-the-antimicrobial-function-of-cellulosic-copper-nanoparticles
#18
Xiaoqing Rong-Mullins, Matthew J Winans, Justin B Lee, Zachery R Lonergan, Vincent A Pilolli, Lyndsey M Weatherly, Thomas W Carmenzind, Lihua Jiang, Jonathan R Cumming, Gloria S Oporto, Jennifer E G Gallagher
Copper (Cu) was used in antiquity to prevent waterborne and food diseases because, as a broad-spectrum antimicrobial agent, it generates reactive oxygen species, ROS. New technologies incorporating Cu into low-cost biodegradable nanomaterials built on cellulose, known as cellulosic cupric nanoparticles or c-CuNPs, present novel approaches to deliver Cu in a controlled manner to control microbial growth. We challenged strains of Saccharomyces cerevisiae with soluble Cu and c-CuNPs to evaluate the potential of c-CuNPs as antifungal agents...
September 20, 2017: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/28862946/%C3%AE-1-adrenergic-receptors-function-within-hetero-oligomeric-complexes-with-atypical-chemokine-receptor-3-and-chemokine-c-x-c-motif-receptor-4-in-vascular-smooth-muscle-cells
#19
Lauren J Albee, Jonathan M Eby, Abhishek Tripathi, Heather M LaPorte, Xianlong Gao, Brian F Volkman, Vadim Gaponenko, Matthias Majetschak
BACKGROUND: Recently, we provided evidence that α1-adrenergic receptors (ARs) in vascular smooth muscle are regulated by chemokine (C-X-C motif) receptor (CXCR) 4 and atypical chemokine receptor 3 (ACKR3). While we showed that CXCR4 controls α1-ARs through formation of heteromeric receptor complexes in human vascular smooth muscle cells (hVSMCs), the molecular basis underlying cross-talk between ACKR3 and α1-ARs is unknown. METHODS AND RESULTS: We show that ACKR3 agonists inhibit inositol trisphosphate production in hVSMCs on stimulation with phenylephrine...
August 17, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/28860469/prolonged-at1r-activation-induces-cav1-2-channel-internalization-in-rat-cardiomyocytes
#20
Tamara Hermosilla, Matías Encina, Danna Morales, Cristian Moreno, Carolina Conejeros, Hilda M Alfaro-Valdés, Felipe Lagos-Meza, Felipe Simon, Christophe Altier, Diego Varela
The cardiac L-type calcium channel is a multi-subunit complex that requires co-assembling of the pore-forming subunit CaV1.2 with auxiliary subunits CaVα2δ and CaVβ. Its traffic has been shown to be controlled by these subunits and by the activation of various G-protein coupled receptors (GPCR). Here, we explore the consequences of the prolonged activation of angiotensin receptor type 1 (AT1R) over CaV1.2 channel trafficking. Bioluminescence Resonance Energy Transfer (BRET) assay between β-arrestin and L-type channels in angiotensin II-stimulated cells was used to assess the functional consequence of AT1R activation, while immunofluorescence of adult rat cardiomyocytes revealed the effects of GPCR activation on CaV1...
August 31, 2017: Scientific Reports
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