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https://www.readbyqxmd.com/read/28431242/structural-and-functional-analysis-of-a-%C3%AE-2-adrenergic-receptor-complex-with-grk5
#1
Konstantin E Komolov, Yang Du, Nguyen Minh Duc, Robin M Betz, João P G L M Rodrigues, Ryan D Leib, Dhabaleswar Patra, Georgios Skiniotis, Christopher M Adams, Ron O Dror, Ka Young Chung, Brian K Kobilka, Jeffrey L Benovic
The phosphorylation of agonist-occupied G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) functions to turn off G-protein signaling and turn on arrestin-mediated signaling. While a structural understanding of GPCR/G-protein and GPCR/arrestin complexes has emerged in recent years, the molecular architecture of a GPCR/GRK complex remains poorly defined. We used a comprehensive integrated approach of cross-linking, hydrogen-deuterium exchange mass spectrometry (MS), electron microscopy, mutagenesis, molecular dynamics simulations, and computational docking to analyze GRK5 interaction with the β2-adrenergic receptor (β2AR)...
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28379541/resistance-to-apoptosis-and-autophagy-leads-to-enhanced-survival-in-sertoli-cells
#2
Ferial Aslani, Tim Sebastian, Miguel Keidel, Suada Fröhlich, Hans-Peter Elsässer, Hans-Christian Schuppe, Jörg Klug, Poornima Mahavadi, Monika Fijak, Martin Bergmann, Andreas Meinhardt, Sudhanshu Bhushan
STUDY QUESTION: What is the underlying mechanism of Sertoli cell (SC) resistance to cell death? SUMMARY ANSWER: High expression of pro-survival B cell lymphoma-2 (BCL2) proteins and inhibition of apoptosis and autophagy prolongs SC survival upon exposure to stress stimuli. WHAT IS KNOWN ALREADY: In human and in experimental models of orchitis, tolerogenic SC survive stress conditions, while germ cells undergo massive apoptosis. In general, non-dividing highly differentiated cells tend to resist stress conditions for a longer time by favoring activation of pro-survival mechanisms and inhibition of cell death pathways...
April 3, 2017: Molecular Human Reproduction
https://www.readbyqxmd.com/read/28334166/grk5-regulates-social-behavior-via-suppression-of-mtorc1-signaling-in-medial-prefrontal-cortex
#3
Bing Niu, Peipei Liu, Minjie Shen, Cao Liu, Li Wang, Feifei Wang, Lan Ma
Impairments in social behaviors are features of a number of psychiatric diseases associated with subtle alterations in the medial prefrontal cortex (mPFC) circuitry. G protein-coupled receptor kinase (GRK) 5 is widely expressing in the cortex, however, its role in regulation of the mPFC activity and the development of social behaviors and psychiatric disorders is unclear. Here, we found that GRK5 dificiency in mice caused social behavior impairments. Further morphological, electrophysiological, and biochemical analyses showed abnormal postsynaptic ultrastructure, impaired excitatory synaptic transmission, the increased association of raptor with mTOR, and overactivated mTORC1-S6K signaling in the mPFC of Grk5-/- mice...
February 27, 2017: Cerebral Cortex
https://www.readbyqxmd.com/read/28328746/cross-talk-between-insulin-signaling-and-gpcrs
#4
Qin Fu, Qian Shi, Toni M West, Yang K Xiang
Diabetes is a major risk factor for the development of heart failure. One of the hallmarks of diabetes is insulin resistance associated with hyperinsulinemia. The literature shows that insulin and adrenergic signaling is intimately linked to each other; however, whether and how insulin may modulate cardiac adrenergic signaling and cardiac function remains unknown. Notably, recent studies have revealed that insulin receptor and β2 adrenergic receptor (β2AR) forms a membrane complex in animal hearts, bringing together the direct contact between two receptor signaling systems, and forming an integrated and dynamic network...
March 17, 2017: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/28328744/non-canonical-roles-of-grks-in-cardiovascular-signaling
#5
Sarah M Schumacher, Walter J Koch
G protein-coupled receptor kinases (GRKs) are classically known for their role in regulating the activity of the largest known class of membrane receptors, which influence diverse biological processes in every cell type in the human body. As researchers have tried to uncover how this family of kinases, containing only 7 members, achieves selective and coordinated control of receptors, they have uncovered a growing number of non-canonical activities for these kinases. These activities include phosphorylation of non-receptor targets and kinase-independent molecular interactions...
March 17, 2017: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/28227032/a-statistical-model-for-stroke-outcome-prediction-and-treatment-planning
#6
Abhishek Sengupta, Vaibhav Rajan, Sakyajit Bhattacharya, G R K Sarma, Abhishek Sengupta, Vaibhav Rajan, Sakyajit Bhattacharya, G R K Sarma, Abhishek Sengupta, Grk Sarma, Vaibhav Rajan, Sakyajit Bhattacharya
Stroke is a major cause of mortality and long-term disability in the world. Predictive outcome models in stroke are valuable for personalized treatment, rehabilitation planning and in controlled clinical trials. We design a new multi-class classification model to predict outcome in the short-term, the putative therapeutic window for several treatments. Our model addresses the challenges of class imbalance, where the training data is dominated by samples of a single class, and highly correlated predictor and outcome variables, which makes learning the effects of treatments on the outcome difficult...
August 2016: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
https://www.readbyqxmd.com/read/28214967/increased-atrial-%C3%AE-adrenergic-receptors-and-grk-2-gene-expression-can-play-a-fundamental-role-in-heart-failure-after-repair-of-congenital-heart-disease-with-cardiopulmonary-bypass
#7
Marcela Silva Oliveira, Fabio Carmona, Walter V A Vicente, Paulo H Manso, Karina M Mata, Mara Rúbia Celes, Erica C Campos, Simone G Ramos
Surgeries to correct congenital heart diseases are increasing in Brazil and worldwide. However, even with the advances in surgical techniques and perfusion, some cases, especially the more complex ones, can develop heart failure and death. A retrospective study of patients who underwent surgery for correction of congenital heart diseases with cardiopulmonary bypass (CPB) in a university tertiary-care hospital that died, showed infarction in different stages of evolution and scattered microcalcifications in the myocardium, even without coronary obstruction...
April 2017: Pediatric Cardiology
https://www.readbyqxmd.com/read/28213524/g-protein-coupled-receptor-kinase-2-grk-2-regulates-serotonin-metabolism-through-the-monoamine-oxidase-amx-2-in-caenorhabditis-elegans
#8
Jianjun Wang, Jiansong Luo, Dipendra K Aryal, William C Wetsel, Richard Nass, Jeffrey L Benovic
G protein-coupled receptors (GPCRs) regulate many animal behaviors. GPCR signaling is mediated by agonist-promoted interactions of GPCRs with heterotrimeric G proteins, GPCR kinases (GRKs), and arrestins. To further elucidate the role of GRKs in regulating GPCR-mediated behaviors, we utilized the genetic model system Caenorhabditis elegans Our studies demonstrate that grk-2 loss-of-function strains are egg laying-defective and contain low levels of serotonin (5-HT) and high levels of the 5-HT metabolite 5-hydroxyindole acetic acid (5-HIAA)...
April 7, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28028441/granzymes-a-and-k-differentially-potentiate-lps-induced-cytokine-response
#9
Annette C Wensink, Helena M Kok, Jan Meeldijk, Job Fermie, Christopher J Froelich, C Erik Hack, Niels Bovenschen
Granzymes are serine proteases that, upon release from cytotoxic cells, induce apoptosis in tumor cells and virally infected cells. In addition, a role of granzymes in inflammation is emerging. Recently, we have demonstrated that extracellular granzyme K (GrK) potentiates lipopolysaccharide (LPS)-induced cytokine response from monocytes. GrK interacts with LPS, disaggregates LPS micelles, and stimulates LPS-CD14 binding and Toll-like receptor signaling. Here we show that human GrA also potentiates cytokine responses in human monocytes initiated by LPS or Gram-negative bacteria...
2016: Cell Death Discovery
https://www.readbyqxmd.com/read/28018974/hypoxia-sensing-through-%C3%AE-adrenergic-receptors
#10
Hoi I Cheong, Kewal Asosingh, Olivia R Stephens, Kimberly A Queisser, Weiling Xu, Belinda Willard, Bo Hu, Josephine Kam Tai Dermawan, George R Stark, Sathyamangla V Naga Prasad, Serpil C Erzurum
Life-sustaining responses to low oxygen, or hypoxia, depend on signal transduction by HIFs, but the underlying mechanisms by which cells sense hypoxia are not completely understood. Based on prior studies suggesting a link between the β-adrenergic receptor (β-AR) and hypoxia responses, we hypothesized that the β-AR mediates hypoxia sensing and is necessary for HIF-1α accumulation. Beta blocker treatment of mice suppressed hypoxia induction of renal HIF-1α accumulation, erythropoietin production, and erythropoiesis in vivo...
December 22, 2016: JCI Insight
https://www.readbyqxmd.com/read/27983752/high-fat-diet-induces-protein-kinase-a-and-g-protein-receptor-kinase-phosphorylation-of-%C3%AE-2-adrenergic-receptor-and-impairs-cardiac-adrenergic-reserve-in-animal-hearts
#11
Qin Fu, Yuting Hu, Qingtong Wang, Yongming Liu, Ning Li, Bing Xu, Sungjin Kim, Nipavan Chiamvimonvat, Yang K Xiang
KEY POINTS: Patients with diabetes show a blunted cardiac inotropic response to β-adrenergic stimulation despite normal cardiac contractile reserve. Acute insulin stimulation impairs β-adrenergically induced contractile function in isolated cardiomyocytes and Langendorff-perfused hearts. In this study, we aimed to examine the potential effects of hyperinsulinaemia associated with high-fat diet (HFD) feeding on the cardiac β2 -adrenergic receptor signalling and the impacts on cardiac contractile function...
March 15, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/27888281/the-actions-of-relaxin-family-peptides-on-signal-transduction-pathways-activated-by-the-relaxin-family-peptide-receptor-rxfp4
#12
COMPARATIVE STUDY
Sheng Y Ang, Dana S Hutchinson, Bronwyn A Evans, Mohammed A Hossain, Nitin Patil, Ross A D Bathgate, Martina Kocan, Roger J Summers
The relaxin family peptide receptor 4 (RXFP4) is a G protein-coupled receptor (GPCR) expressed in the colorectum with emerging roles in metabolism and appetite regulation. It is activated by its cognate ligand insulin-like peptide 5 (INSL5) that is expressed in enteroendocrine L cells in the gut. Whether other evolutionarily related peptides such as relaxin-2, relaxin-3, or INSL3 activate RXFP4 signal transduction mechanisms with a pattern similar to or distinct from INSL5 is still unclear. In this study, we compare the signaling pathways activated by various relaxin family peptides to INSL5...
January 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/27753817/ssa-05-4-differences-in-management-of-hypertension-between-ethnic-groups
#13
Brian Rayner
Although the consequences of hypertension are universal, Blacks (African Americans or Indigenous Africans) have been the subject of a differential approach to causation, outcome and treatment. Blacks have a greater propensity to salt sensitivity and suppressed plasma renin suggesting a predisposition to Na retention by the kidney. As a result blood pressure (BP) response to diuretics and amlodipine is better than inhibitors of the renin-angiotensin-system in monotherapy. Target organ damage is more frequent and blood pressure (BP) is more difficult to control despite more intensive therapy...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27643380/ssa-05-4-differences-in-management-of-hypertension-between-ethnic-groups
#14
Brian Rayner
Although the consequences of hypertension are universal, Blacks (African Americans or Indigenous Africans) have been the subject of a differential approach to causation, outcome and treatment. Blacks have a greater propensity to salt sensitivity and suppressed plasma renin suggesting a predisposition to Na retention by the kidney. As a result blood pressure (BP) response to diuretics and amlodipine is better than inhibitors of the renin-angiotensin-system in monotherapy. Target organ damage is more frequent and blood pressure (BP) is more difficult to control despite more intensive therapy...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27609978/specific-immune-cell-and-cytokine-characteristics-of-human-testicular-germ-cell-neoplasia
#15
Britta Klein, Thomas Haggeney, Daniela Fietz, Sivanjah Indumathy, Kate L Loveland, Mark Hedger, Sabine Kliesch, Wolfgang Weidner, Martin Bergmann, Hans-Christian Schuppe
STUDY QUESTION: Which immune cells and cytokine profiles are characteristic for testicular germ cell neoplasia and what consequences does this have for the understanding of the related testicular immunopathology? SUMMARY ANSWER: The unique immune environment of testicular germ cell neoplasia comprises B cells and dendritic cells as well as high transcript levels of IL-6 and other B cell supporting or T helper cell type 1 (Th1)-driven cytokines and thus differs profoundly from normal testis or inflammatory lesions associated with hypospermatogenesis...
October 2016: Human Reproduction
https://www.readbyqxmd.com/read/27573285/regulatory-effects-of-grk2-on-gpcrs-and-non-gpcrs-and-possible-use-as-a-drug-target-review
#16
REVIEW
Chen-Chen Han, Yang Ma, Yifan Li, Yang Wang, Wei Wei
G protein-coupled receptor kinase 2 (GRK2) is a key member of the G protein-coupled receptor kinase (GRK) family. GRK2 activity is regulated by the C-terminus of GRK2 which contains a plekstrin homology domain and the N-terminus of GRK2 which contains the RGS homology domain with binding sites for several proteins and lipids such as G protein-coupled receptors (GPCRs), G protein, phospholipase C, phosphatidylinositol 4,5-bisphosphate, extracellular signal‑regulated kinase, protein kinase A and Gβγ...
October 2016: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/27572922/c-terminal-residues-specific-to-vasa-among-dead-box-helicases-are-required-for-its-functions-in-pirna-biogenesis-and-embryonic-patterning
#17
Mehrnoush Dehghani, Paul Lasko
The DEAD-box RNA helicase Vasa (Vas, also known as DDX4) is required for germ cell development. In Drosophila, analysis of hypomorphic mutations has implicated maternally expressed Vas in germ cell formation and posterior embryonic patterning. vas-null females, which rarely complete oogenesis, exhibit defects in mitotic progression of germline stem cells, Piwi-interacting RNA (piRNA)-mediated transposon silencing, and translation of Gurken (Grk), an EGFR ligand. The carboxy-terminal region of Vas orthologs throughout the animal kingdom consists of several acidic residues as well as an invariant tryptophan in the penultimate or ultimate position (Trp660 in Drosophila melanogaster)...
November 2016: Development Genes and Evolution
https://www.readbyqxmd.com/read/27565865/grk5-knockout-mice-generated-by-talen-mediated-gene-targeting
#18
Tsevelmaa Nanjidsuren, Chae-Won Park, Bo-Woong Sim, Sun-Uk Kim, Kyu-Tae Chang, Myung-Hwa Kang, Kwan-Sik Min
Transcription activator-like effector nucleases (TALENs) are a new type of engineered nuclease that is very effective for directed gene disruption in any genome sequence. We investigated the generation of mice with genetic knockout (KO) of the G protein-coupled receptor kinase (GRK) 5 gene by microinjection of TALEN mRNA. TALEN vectors were designed to target exons 1, 3, and 5 of the mouse GRK5 gene. Flow cytometry showed that the activity of the TALEN mRNAs targeted to exons 1, 3, and 5 was 8.7%, 9.7%, and 12...
October 2016: Animal Biotechnology
https://www.readbyqxmd.com/read/27541735/cardiac-%C3%AE-2-adrenergic-receptor-phosphorylation-at-ser355-356-regulates-receptor-internalization-and-functional-resensitization
#19
Xiaofang Fan, Xuejiang Gu, Ru Zhao, Qingqing Zheng, Lan Li, Wenbing Yang, Lu Ding, Feng Xue, Junming Fan, Yongsheng Gong, Yongyu Wang
Previous studies have demonstrated that β2-adrenergic receptors (β2ARs) can be phosphorylated by G protein-coupled receptor kinases (GRKs) and protein kinase A (PKA), affecting β2AR internalization and desensitization. However, the exact physiological function of β2ARs in cardiomyocytes is unknown. In this study, we showed that neonatal mouse cardiomyocytes had different contraction and internalization responses to sustained or repeated, transient agonist stimulation. Specifically, short-time stimulation (10 min) with epinephrine or norepinephrine increased the cardiomyocyte contraction rate, reaching a maximum at 5 min, followed by a slow decline...
2016: PloS One
https://www.readbyqxmd.com/read/27378756/chapter-three-ubiquitination-and-protein-turnover-of-g-protein-coupled-receptor-kinases-in-gpcr-signaling-and-cellular-regulation
#20
P Penela
G-protein-coupled receptors (GPCRs) are responsible for regulating a wide variety of physiological processes, and distinct mechanisms for GPCR inactivation exist to guarantee correct receptor functionality. One of the widely used mechanisms is receptor phosphorylation by specific G-protein-coupled receptor kinases (GRKs), leading to uncoupling from G proteins (desensitization) and receptor internalization. GRKs and β-arrestins also participate in the assembly of receptor-associated multimolecular complexes, thus initiating alternative G-protein-independent signaling events...
2016: Progress in Molecular Biology and Translational Science
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