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Mei-Yi Lu, Syuan-Shao Lu, Shiann-Luen Chang, Fang Liao
CCR6 is a G protein-coupled receptor (GPCR) that recognizes a single chemokine ligand, CCL20 and is primarily expressed by leukocytes. Upon ligand binding, CCR6 activates Gαi heterotrimeric G proteins to induce various potential cellular outcomes through context-specific cell signaling. It is well known that differential phosphorylation of Ser and Thr residues in the C-terminal domains or intracellular loops of GPCRs can generate barcodes that regulate GPCR function by regulating the recruitment of β-arrestins...
2018: Frontiers in Immunology
Graeme Milligan, Asuka Inoue
Rapid developments in genome editing, based largely on CRISPR/Cas9 technologies, are offering unprecedented opportunities to eliminate the expression of single or multiple gene products in intact organisms and in model cell systems. Elimination of individual G protein-coupled receptors (GPCRs), both single and multiple G protein subunits, and arrestin adaptor proteins is providing new and sometimes unanticipated insights into molecular details of the regulation of cell signalling pathways and the behaviour of receptor ligands...
March 13, 2018: Trends in Pharmacological Sciences
David M Thal, Ziva Vuckovic, Christopher J Draper-Joyce, Yi-Lynn Liang, Alisa Glukhova, Arthur Christopoulos, Patrick M Sexton
G protein-coupled receptors (GPCRs) are the largest superfamily of cell surface receptor proteins and are important drug targets for many human diseases. In the last decade, remarkable progress has been made in the determination of atomic structures of GPCRs with over 200 structures from 53 unique receptors having been solved. Technological advances in protein engineering and X-ray crystallography have driven much of the progress to date. However, recent advances in cryo-electron microscopy have facilitated the structural determination of three new structures of active-state GPCRs in complex with heterotrimeric G protein...
March 13, 2018: Current Opinion in Structural Biology
Élie Besserer-Offroy, Patrick Bérubé, Jérôme Côté, Alexandre Murza, Jean-Michel Longpré, Robert Dumaine, Olivier Lesur, Mannix Auger-Messier, Richard Leduc, Éric Marsault, Philippe Sarret
The apelinergic system is an important player in the regulation of both vascular tone and cardiovascular function, making this physiological system an attractive target for drug development for hypertension, heart failure and ischemic heart disease. Indeed, apelin exerts a positive inotropic effect in humans whilst reducing peripheral vascular resistance. In this study, we investigated the signaling pathways through which apelin exerts its hypotensive action. We synthesized a series of apelin-13 analogs whereby the C-terminal Phe13 residue was replaced by natural or unnatural amino acids...
March 9, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Martyna Szpakowska, Max Meyrath, Nathan Reynders, Manuel Counson, Julien Hanson, Jan Steyaert, Andy Chevigné
The atypical chemokine receptor ACKR3/CXCR7 plays crucial roles in numerous physiological processes but also in viral infection and cancer. ACKR3 shows strong propensity for activation and, unlike classical chemokine receptors, can respond to chemokines from both the CXC and CC families as well as to the endogenous peptides BAM22 and adrenomedullin. Moreover, despite belonging to the G protein coupled receptor family, its function appears to be mainly dependent on β-arrestin. ACKR3 has also been shown to continuously cycle between the plasma membrane and the endosomal compartments, suggesting a possible role as a scavenging receptor...
March 9, 2018: Biochemical Pharmacology
N Dietis, H Niwa, R Tose, J McDonald, V Ruggieri, M Filaferro, G Vitale, L Micheli, C Ghelardini, S Salvadori, G Calo, R Guerrini, D J Rowbotham, D G Lambert
BACKGROUND AND PURPOSE: Targeting more than one opioid receptor type simultaneously may have analgesic advantages in reduced side effect profile. We have evaluated the mixed MOP (μ, mu) agonist/DOP (δ, delta) antagonist UFP-505 in vitro and in vivo. EXPERIMENTAL APPROACH: We measured receptor density and function in single MOP, DOP and MOP/DOP double expression systems. GTPγ35 S binding, cAMP formation and arrestin recruitment were measured. Antinociceptive activity was measured in vivo using tail withdrawal and paw pressure tests following acute and chronic treatment...
March 10, 2018: British Journal of Pharmacology
Jia Zhang, Jiming Yin, Yangjia Wang, Bin Li, Xiangjun Zeng
The cause of the invalid reaction of smooth muscle cells to mechanical stimulation that results in a dysfunctional myogenic response that mediates the disruption of renal blood flow (RBF) in diabetic patients is debatable. The present study revealed that increased apelin concentration in serum of diabetic mice neutralized the myogenic response mediated by apelin receptor (APJ) and resulted in increased RBF, which promoted the progression of diabetic nephropathy. The results showed that apelin concentration, RBF, and albuminuria:creatinine ratio were all increased in kkAy mice, and increased RBF correlated positively to serum apelin both in C57 and diabetic mice...
March 9, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Lani S Chun, Rakesh H Vekariya, R Benjamin Free, Yun Li, Da-Ting Lin, Ping Su, Fang Liu, Yoon Namkung, Stephane A Laporte, Amy E Moritz, Jeffrey Aubé, Kevin J Frankowski, David R Sibley
The dopamine D2 receptor (D2R) is known to elicit effects through activating two major signaling pathways mediated by either G proteins (Gi/o) or β-arrestins. However, the specific role of each pathway in physiological or therapeutic activities is not known with certainty. One approach to the dissection of these pathways is through the use of drugs that can selectively modulate one pathway vs. the other through a mechanism known as functional selectivity or biased signaling. Our laboratory has previously described a G protein signaling-biased agonist, MLS1547, for the D2R using a variety of in vitro functional assays...
2018: Frontiers in Synaptic Neuroscience
Junie Hovsepian, Véronique Albanèse, Michel Becuwe, Vasyl Ivashov, David Teis, Sébastien Léon
Yeast cells have a remarkable ability to adapt to nutritional changes in their environment. During adaptation, nutrient-signalling pathways drive the selective endocytosis of nutrient transporters present at the cell surface. A current challenge is to understand the mechanistic basis of this regulation. Transporter endocytosis is triggered by their ubiquitylation, which involves the ubiquitin ligase Rsp5 and its adaptors of the arrestin-related family (ART). This step is highly regulated by nutrient availability...
March 7, 2018: Molecular Biology of the Cell
Qiyu Wang, Jiujiu Yu, Tatenda Kadungure, Joseph Beyene, Hong Zhang, Quan Lu
Majority of disease-modifying therapeutic targets are restricted to the intracellular space and are therefore not druggable using existing biologic modalities. The ability to efficiently deliver macromolecules inside target cells or tissues would greatly expand the current landscape of therapeutic targets for future generations of biologic drugs, but remains challenging. Here we report the use of extracellular vesicles, known as arrestin domain containing protein 1 [ARRDC1]-mediated microvesicles (ARMMs), for packaging and intracellular delivery of a myriad of macromolecules, including the tumor suppressor p53 protein, RNAs, and the genome-editing CRISPR-Cas9/guide RNA complex...
March 6, 2018: Nature Communications
Hebatullah Laban, Andreas Weigert, Joana Zink, Amro Elgheznawy, Christoph Schürmann, Lea Günther, Randa Abdel Malik, Sabrina Bothur, Susanne Wingert, Rolf Bremer, Michael A Rieger, Bernhard Brüne, Ralf P Brandes, Ingrid Fleming, Peter M Benz
In ischemic vascular diseases, leukocyte recruitment and polarization are crucial for revascularization and tissue repair. We investigated the role of vasodilator-stimulated phosphoprotein (VASP) in vascular repair. After hindlimb ischemia induction, blood flow recovery, angiogenesis, arteriogenesis, and leukocyte infiltration into ischemic muscles in VASP-/- mice were accelerated. VASP deficiency also elevated the polarization of the macrophages through increased signal transducer and activator of transcription (STAT) signaling, which augmented the release of chemokines, cytokines, and growth factors to promote leukocyte recruitment and vascular repair...
March 5, 2018: Journal of Cell Biology
Brandon H Kim, Alexey Pereverzev, Shuying Zhu, Abby Oi Man Tong, S Jeffrey Dixon, Peter Chidiac
Parathyroid hormone (PTH) activates the PTH/PTH-related peptide receptor (PTH1R) on osteoblasts and other target cells. Mechanical stimulation of cells, including osteoblasts, causes release of nucleotides such as ATP into the extracellular fluid. In addition to its role as an energy source, ATP serves as an agonist at P2 receptors and an allosteric regulator of many proteins. We investigated the effects of concentrations of extracellular ATP, comparable to those that activate low affinity P2X7 receptors, on PTH1R signaling...
March 1, 2018: Cellular Signalling
Yasumasa Mototani, Tadashi Okamura, Motohito Goto, Yukiko Shimizu, Rieko Yanobu-Takanashi, Aiko Ito, Naoya Kawamura, Yuka Yagisawa, Daisuke Umeki, Megumi Nariyama, Kenji Suita, Yoshiki Ohnuki, Kouichi Shiozawa, Yoshinori Sahara, Tohru Kozasa, Yasutake Saeki, Satoshi Okumura
The G protein-regulated inducer of neurite growth (GRIN) family has three isoforms (GRIN1-3), which bind to the Gαi/o subfamily of G protein that mediate signal processing via G protein-coupled receptors (GPCRs). Here, we show that GRIN3 is involved in regulation of dopamine-dependent behaviors and is essential for activation of the dopamine receptors (DAR)-β-arrestin signaling cascade. Analysis of functional regions of GRIN3 showed that a di-cysteine motif (Cys751/752) is required for plasma membrane localization...
March 2, 2018: Pflügers Archiv: European Journal of Physiology
Sheela Verjee, Anna Weston, Christiane Kolb, Heba Kalbhenn-Aziz, Veronika Butterweck
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis plays an important part in the development of depressive symptoms. In this study, the effects of a commercial St. John's wort extract (STW3-VI), hyperforin, miquelianin, and the selective serotonin reuptake inhibitor citalopram on the expression of genes relevant to HPA axis function were investigated in human neuronal cells. SH-SY5Y cells were treated with STW3-VI (20 µg/mL), hyperforin (1 µM), miquelianin (10 µM), or citalopram (10 µM) in the presence of the glucocorticoid receptor agonist dexamethasone (DEX,10 µM) for 6 h and 48 h, respectively...
March 2, 2018: Planta Medica
Akshay Bareja, Shubham Patel, Conrad P Hodgkinson, Alan Payne, Victor J Dzau
The development of biased agonist drugs is widely recognized to be important for the treatment of many diseases, including cardiovascular disease. While GPCR biased agonism has been heavily characterized there is a distinct lack of information with respect to RTK biased agonism both in the identification of biased agonists as well as their attendant mechanisms. One such RTK, the Insulin-like Growth Factor 1 Receptor (IGF1R) plays an important role in a range of biological and disease processes. The micropeptide LL37 has been described as a biased agonist of the IGF1R...
February 27, 2018: Cellular Signalling
Sarah C Erlandson, Conor McMahon, Andrew C Kruse
G protein-coupled receptors (GPCRs), which mediate processes as diverse as olfaction and maintenance of metabolic homeostasis, have become the single most effective class of therapeutic drug targets. As a result, understanding the molecular basis for their activity is of paramount importance. Recent technological advances have made GPCR structural biology increasingly tractable, offering views of these receptors in unprecedented atomic detail. Structural and biophysical data have shown that GPCRs function as complex allosteric machines, communicating ligand-binding events through conformational change...
March 2, 2018: Annual Review of Biophysics
Wenhui Li, Jiachao Xu, Xiaolong Kou, Rong Zhao, Wei Zhou, Xiaohong Fang
Angiotensin II type 1 receptor (AT1R), a typical G protein-coupled receptor, plays a key role in regulating many cardiovascular functions. Different ligands can bind with AT1R to selectively activate either G protein (Gq) or β-arrestin (β-arr) pathway, or both pathways, but the molecular mechanism is not clear yet. In this work, we used, for the first time, atomic force microscopy-based single molecule force spectroscopy (SMFS) to study the interactions of AT1R with three types of ligands, balanced ligand, Gq-biased ligand, and β-arr-biased ligand, in living cells...
February 28, 2018: Analytical and Bioanalytical Chemistry
Thomas F Pack, Margo I Orlen, Caroline Ray, Sean M Peterson, Marc G Caron
The dopamine D2 receptor (D2R) is a G protein-coupled receptor (GPCR) that is critical for many central nervous system functions. The D2R carries out these functions by signaling through two transducers: G proteins and β-arrestins (βarrs). Selectively engaging either the G protein or βarr pathway may be a way to improve drugs targeting GPCRs. The current model of GPCR signal transduction posits a chain of events where G protein activation ultimately leads to βarr recruitment. GPCR kinases (GRKs), which are regulated by G proteins and whose kinase action facilitates βarr recruitment, bridge these pathways...
February 27, 2018: Journal of Biological Chemistry
Gemma Navarro, Arnau Cordomí, Marc Brugarolas, Estefanía Moreno, David Aguinaga, Laura Pérez-Benito, Sergi Ferre, Antoni Cortés, Vicent Casadó, Josefa Mallol, Enric I Canela, Carme Lluís, Leonardo Pardo, Peter J McCormick, Rafael Franco
BACKGROUND: G-protein-coupled receptor (GPCR) heteromeric complexes have distinct properties from homomeric GPCRs, giving rise to new receptor functionalities. Adenosine receptors (A1 R or A2A R) can form A1 R-A2A R heteromers (A1 -A2A Het), and their activation leads to canonical G-protein-dependent (adenylate cyclase mediated) and -independent (β-arrestin mediated) signaling. Adenosine has different affinities for A1 R and A2A R, allowing the heteromeric receptor to detect its concentration by integrating the downstream Gi - and Gs -dependent signals...
February 28, 2018: BMC Biology
Juan Li, Ao Guo, Qinying Wang, Yuanyuan Li, Jian Zhao, Jing Lu, Gang Pei
β-Arrestins (β-arrestin-1 and -2) are multifunctional proteins that play important roles in the regulation of inflammation and cell survival that need to be tightly controlled; however, the mechanism that underlies their gene expression is largely unclear. Here, we demonstrate that β-arrestin-1 is a transcriptional target of NF-κB. mRNA and protein levels of β-arrestin-1 were up-regulated by NF-κB inducers. Inhibition of NF-κB prevented the up-regulation of β-arrestin-1 mRNA, whereas activation of NF-κB led to increased β-arrestin-1 expression...
February 27, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
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