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Ursula Quitterer, Xuebin Fu, Armin Pohl, Karam M Bayoumy, Andreas Langer, Said AbdAlla
Preeclampsia is the most frequent pregnancy-related complication worldwide with no cure. While a number of molecular features have emerged, the underlying causal mechanisms behind the disorder remain obscure. Here, we find that increased complex formation between angiotensin II AT1 and bradykinin B2, two G protein-coupled receptors with opposing effects on blood vessel constriction, triggers symptoms of preeclampsia in pregnant mice. Aberrant heteromerization of AT1-B2 led to exaggerated calcium signaling and high vascular smooth muscle mechanosensitivity, which could explain the onset of preeclampsia symptoms at late-stage pregnancy as mechanical forces increase with fetal mass...
November 20, 2018: Cell
Shaona Niu, Hui Li, Wenbin Chen, Jiajun Zhao, Ling Gao, Tao Bo
[This corrects the article DOI: 10.1155/2018/4371396.].
2018: International Journal of Endocrinology
Victoria El-Khoury, Mélanie Béland, Anna Schritz, Sang-Yoon Kim, Petr V Nazarov, Louis Gaboury, Katriina Sertamo, François Bernardin, Roxane Batutu, Laurent Antunes, Catherine W Bennett, François Faÿs, Guy Berchem, Yeoun Jin Kim
BACKGROUND: Distinguishing lung adenocarcinoma (ADC) from squamous cell carcinoma (SCC) has a tremendous therapeutic implication. Sometimes, the commonly used immunohistochemistry (IHC) markers fail to discriminate between them, urging for the identification of new diagnostic biomarkers. METHODS: We performed IHC on tissue microarrays from two cohorts of lung cancer patients to analyse the expression of beta-arrestin-1, beta-arrestin-2 and clinically used diagnostic markers in ADC and SCC samples...
August 6, 2018: British Journal of Cancer
Antonella Rigo, Isacco Ferrarini, Giulio Innamorati, Fabrizio Vinante
CXCL12/CXCR4 axis relies on both heterotrimeric Gi protein and β-arrestin coupling to trigger downstream responses. G protein activation allows for calcium flux, chemotaxis and early extracellular-signal regulated kinases 1/2 (ERK1/2) phosphorylation, whereas β-arrestin recruitment leads to late signaling, receptor desensitization and internalization. Together they may regulate the balance between transactivation and transinhibition of epithelial growth factor receptor 1 (HER1). Since we have previously noted significant differences between CXCL12 and its structural variant [N33A]CXCL12 in CXCR4 signaling, we sought to better characterize them by performing cAMP inhibition and β-arrestin recruitment assays, as well as functional tests that separately investigate G protein and β-arrestin-induced responses...
June 22, 2018: Oncotarget
Richard Ågren, Peter Århem, Johanna Nilsson, Kristoffer Sahlholm
Background: Previous evidence suggests that UNC9994 is a beta-arrestin2-selective agonist at the dopamine D2 receptor (D2R), lacking ability both to activate and to antagonize G protein-dependent signaling. However, this has only been reported by one laboratory using a single assay. Methods: We used G protein-coupled inward rectifier potassium channel (GIRK) activation in Xenopus oocytes to investigate UNC9994-induced modulation of G protein-dependent signaling at D2R and D3R...
July 6, 2018: International Journal of Neuropsychopharmacology
M Young, T Dahoun, B Sokrat, C Arber, K M Chen, M Bouvier, P Barth
Membrane receptors regulate numerous intracellular functions. However, the molecular underpinnings remain poorly understood because most receptors initiate multiple signaling pathways through distinct interaction interfaces that are structurally uncharacterized. We present an integrated computational and experimental approach to model and rationally engineer membrane receptor-intracellular protein systems signaling with novel pathway selectivity. We targeted the dopamine D2 receptor (D2), a G-protein-coupled receptor (GPCR), which primarily signals through Gi, but triggers also the Gq and beta-arrestin pathways...
July 3, 2018: Proceedings of the National Academy of Sciences of the United States of America
Fei Zheng, Fei Xiao, Qing-Hong Yuan, Qiang-Sheng Liu, Zong-Ze Zhang, Yan-Lin Wang, Jia Zhan
Penehyclidine hydrochloride (PHC), a type of hyoscyamus drug, has both antimuscarinic and antinicotinic activities and retains potent central and peripheral anticholinergic activities. Compared with other hyoscyamine, the notable advantage of PHC is that it has few M2 receptor-associated cardiovascular side effects. Recent studies and clinical trials have suggested that treatment with penehyclidine hydrochloride may also possess good effects in the treatment of lung injury. The mechanism responsible for this effect has yet to be determined; however, one possibility is that they might do so by a direct effect on pulmonary vascular endothelium...
October 2018: Inflammation
Wen-Ting Peng, Wu-Yi Sun, Xin-Ran Li, Jia-Chang Sun, Jia-Jia Du, Wei Wei
Among a great variety of cell surface receptors, the largest superfamily is G protein-coupled receptors (GPCRs), also known as seven-transmembrane domain receptors. GPCRs can modulate diverse signal-transduction pathways through G protein-dependent or independent pathways which involve β-arrestins, G protein receptor kinases (GRKs), ion channels, or Src kinases under physiological and pathological conditions. Recent studies have revealed the crucial role of GPCRs in the tumorigenesis and the development of cancer metastasis...
May 4, 2018: International Journal of Molecular Sciences
Mellar P Davis, Carlos Fernandez, Sally Regel, Mary Lynn McPherson
Nalbuphine has been commercially available for 40 years for the treatment of acute pain; few studies have centered on management of chronic pain. Nalbuphine unique pharmacology is an advantage in pain management. It is µ antagonist, partial κ agonist for G-proteins and beta-arrestin-2. Benefits are related to G-protein interactions resulting in less nausea, pruritus, and respiratory depression than morphine. At low doses, nalbuphine reduces side effects particularly respiratory depression without loss of analgesia when combined with potent opioids...
March 2018: Journal of Opioid Management
Baohai Liu, Shuangdi Li, Xiaodan Sui, Lianyi Guo, Xingmei Liu, Hongmei Li, Leming Gao, Shusheng Cai, Yanrong Li, Tingting Wang, Xuehua Piao
Background: Polygonum cuspidatum Siebold & Zucc. (PCS) has antibacterial properties and may prevent Ulcerative colitis (UC) but related molecular mechanism remains unknown. NF-κB signaling pathway is associated with inflammatory responses and its inactivation may be critical for effective therapy of UC. Methods: UC mouse (C57BL/6J) model was established by using dextran sulfate sodium (DSS). The extract of PCS (PCSE) was prepared by using ethanol and its main ingredients were measured by HPLC. Thirty-two UC mice were evenly assigned into DG (received vehicle control), LG (0...
2018: Frontiers in Pharmacology
Manuel Grundmann, Nicole Merten, Davide Malfacini, Asuka Inoue, Philip Preis, Katharina Simon, Nelly Rüttiger, Nicole Ziegler, Tobias Benkel, Nina Katharina Schmitt, Satoru Ishida, Ines Müller, Raphael Reher, Kouki Kawakami, Ayumi Inoue, Ulrike Rick, Toni Kühl, Diana Imhof, Junken Aoki, Gabriele M König, Carsten Hoffmann, Jesus Gomeza, Jürgen Wess, Evi Kostenis
G protein-independent, arrestin-dependent signaling is a paradigm that broadens the signaling scope of G protein-coupled receptors (GPCRs) beyond G proteins for numerous biological processes. However, arrestin signaling in the collective absence of functional G proteins has never been demonstrated. Here we achieve a state of "zero functional G" at the cellular level using HEK293 cells depleted by CRISPR/Cas9 technology of the Gs/q/12 families of Gα proteins, along with pertussis toxin-mediated inactivation of Gi/o...
January 23, 2018: Nature Communications
Hanna Karakuła-Juchnowicz, Joanna Róg, Dariusz Juchnowicz, Justyna Morylowska-Topolska
G protein-coupled receptors (GPCRs) constitute a family of transmembrane proteins that mediate many cellular processes. GPR120/FFAR4, a receptor from this family that is activated by fatty acids, has received considerable attention recently. This paper presents a literature review concerning the role of GPR120 and its mechanism of action in animal and human studies as well as the potential use of GPR120 for the treatment of chronic diseases. Two electronic databases - Medline and Google Scholar - were searched for available studies addressing the review topic that were written in English and published from 2000 to June 2017...
November 19, 2017: Postȩpy Higieny i Medycyny Doświadczalnej
Nitish Mittal, Ani Minasyan, Nicole Romaneschi, Joshua K Hakimian, Gabriel Gonzalez-Fernandez, Ralph Albert, Nina Desai, Ian A Mendez, Timothy Schallert, Sean B Ostlund, Wendy Walwyn
The two highly homologous non-visual arrestins, beta-arrestin 1 and 2, are ubiquitously expressed in the central nervous system, yet knowledge of their disparate roles is limited. While beta-arrestin 2 (βarr2) has been implicated in several aspects of reward-related learning and behavior, very little is known about the behavioral function of beta-arrestin 1 (βarr1). Using mice lacking βarr1, we focused on the role of this scaffolding and signal transduction protein in reward-motivated behaviors and in striatal glutamatergic function...
2017: PloS One
Eshan Ghosh, Ashish Srivastava, Mithu Baidya, Punita Kumari, Hemlata Dwivedi, Kumari Nidhi, Ravi Ranjan, Shalini Dogra, Akiko Koide, Prem N Yadav, Sachdev S Sidhu, Shohei Koide, Arun K Shukla
Beta-arrestins (βarrs) critically mediate desensitization, endocytosis and signalling of G protein-coupled receptors (GPCRs), and they scaffold a large number of interaction partners. However, allosteric modulation of their scaffolding abilities and direct targeting of their interaction interfaces to modulate GPCR functions selectively have not been fully explored yet. Here we identified a series of synthetic antibody fragments (Fabs) against different conformations of βarrs from phage display libraries. Several of these Fabs allosterically and selectively modulated the interaction of βarrs with clathrin and ERK MAP kinase...
December 2017: Nature Nanotechnology
Carlos Nogueras-Ortiz, Cristina Roman-Vendrell, Gabriel E Mateo-Semidey, Yu-Hsien Liao, Debra A Kendall, Guillermo A Yudowski
G protein-coupled receptors mediate their complex functions through activation of signaling cascades from receptors localized at the cell surface and endosomal compartments. These signaling pathways are modulated by heterotrimeric G proteins and the scaffold proteins beta-arrestin 1 and 2. However, in contrast to the events occurring at the cell surface, our knowledge of the mechanisms controlling signaling from receptors localized at intracellular compartments is still very limited. Here we sought to investigate the intracellular signaling from cannabinoid 2 receptor (CB2 R)...
November 15, 2017: Molecular Biology of the Cell
S Fs Melo, V G Barauna, T Fernandes, E C Carmo, C Ro Carvalho, E M Oliveira
AT(1) receptor (AT1R) blockade prevents physiological cardiac hypertrophy induced by resistance training. Also, our group showed that a single bout of resistance exercise (RE) activates the AKT/mTOR which was also inhibited by AT1R blocker. Here, we investigated whether IGF1-receptor (IGF1-R) and MAPKs were also activated after a single bout of RE. Wistar rats were divided into Sedentary (Sed), Sedentary treated with losartan (Sed+LOS), Exercise (EX), and Exercise treated with losartan (EX+LOS). Cardiac tissue was obtained 5 and 30 min after 4 sets of 12 repetitions of squat exercise (80 % 1RM)...
December 20, 2017: Physiological Research
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...
February 2018: Cellular and Molecular Life Sciences: CMLS
Flavia M Cerniello, Oscar A Carretero, Nadia A Longo Carbajosa, Bruno D Cerrato, Robson A Santos, Hernán E Grecco, Mariela M Gironacci
The MAS1 receptor (R) exerts protective effects in the brain, heart, vessels, and kidney. R trafficking plays a critical function in signal termination and propagation and in R resensitization. We examined MAS1R internalization and trafficking on agonist stimulation and the role of β-arrestin2 in the activation of ERK1/2 (extracellular signal-regulated kinase 1/2) and Akt after MAS1R stimulation. Human embryonic kidney 293T cells were transfected with the coding sequence for MAS1R-YFP (MAS1R fused to yellow fluorescent protein)...
November 2017: Hypertension
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 β1 AR (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...
November 2017: Hypertension
Laura Rosanò, Roberta Cianfrocca, Rosanna Sestito, Piera Tocci, Valeriana Di Castro, Anna Bagnato
Endothelin-1 receptor (ET-1R)/β-arrestin1 (β-arr1) signaling is dysregulated in ovarian cancer. This signaling circuit enables cancer cells to engage several signaling and transcriptional networks that are pervasively intertwined, and represent a potential therapeutic target for developing novel agents for ovarian cancer treatment. Areas covered: In this article, we discuss the role of the signaling network between ET-1R and key pathways mediated by the scaffold protein β-arr1, as part of signaling complex, or as a transcription co-activator, promoting precise control of transcription of different genes, including ET-1...
October 2017: Expert Opinion on Therapeutic Targets
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