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Critical role of the finger loop in arrestin binding to the receptors.
Zheng C, Tholen J, Gurevich VV
(2019) PLoS One 14: e0213792
MeSH Terms: Amino Acid Sequence, Arrestins, HEK293 Cells, Humans, Point Mutation, Protein Conformation, Receptor, Muscarinic M2, Receptors, Adrenergic, beta-2, Receptors, Dopamine D1, Receptors, Dopamine D2, Sequence Homology
Show Abstract · Added March 18, 2020
We tested the interactions with four different G protein-coupled receptors (GPCRs) of arrestin-3 mutants with substitutions in the four loops, three of which contact the receptor in the structure of the arrestin-1-rhodopsin complex. Point mutations in the loop at the distal tip of the N-domain (Glu157Ala), in the C-loop (Phe255Ala), back loop (Lys313Ala), and one of the mutations in the finger loop (Gly65Pro) had mild variable effects on receptor binding. In contrast, the deletion of Gly65 at the beginning of the finger loop reduced the binding to all GPCRs tested, with the binding to dopamine D2 receptor being affected most dramatically. Thus, the presence of a glycine at the beginning of the finger loop appears to be critical for the arrestin-receptor interaction.
0 Communities
1 Members
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MeSH Terms
Skeletal Colonization by Breast Cancer Cells Is Stimulated by an Osteoblast and β2AR-Dependent Neo-Angiogenic Switch.
Mulcrone PL, Campbell JP, Clément-Demange L, Anbinder AL, Merkel AR, Brekken RA, Sterling JA, Elefteriou F
(2017) J Bone Miner Res 32: 1442-1454
MeSH Terms: Animals, Bone and Bones, Breast Neoplasms, Cell Line, Tumor, Coculture Techniques, Female, Humans, Mice, Mice, Knockout, Neoplasm Metastasis, Neoplasm Proteins, Neovascularization, Pathologic, Osteoblasts, Receptors, Adrenergic, beta-2, Vascular Endothelial Growth Factor A
Show Abstract · Added April 26, 2017
The skeleton is a common site for breast cancer metastasis. Although significant progress has been made to manage osteolytic bone lesions, the mechanisms driving the early steps of the bone metastatic process are still not sufficiently understood to design efficacious strategies needed to inhibit this process and offer preventative therapeutic options. Progression and recurrence of breast cancer, as well as reduced survival of patients with breast cancer, are associated with chronic stress, a condition known to stimulate sympathetic nerve outflow. In this study, we show that stimulation of the beta 2-adrenergic receptor (β2AR) by isoproterenol, used as a pharmacological surrogate of sympathetic nerve activation, led to increased blood vessel density and Vegf-a expression in bone. It also raised levels of secreted Vegf-a in osteoblast cultures, and accordingly, the conditioned media from isoproterenol-treated osteoblast cultures promoted new vessel formation in two ex vivo models of angiogenesis. Blocking the interaction between Vegf-a and its receptor, Vegfr2, blunted the increase in vessel density induced by isoproterenol. Genetic loss of the β2AR globally, or specifically in type 1 collagen-expressing osteoblasts, diminished the increase in Vegf-positive osteoblast number and bone vessel density induced by isoproterenol, and reduced the higher incidence of bone metastatic lesions induced by isoproterenol after intracardiac injection of an osteotropic variant of MDA-MB-231 breast cancer cells. Inhibition of the interaction between Vegf-a and Vegfr2 with the blocking antibody mcr84 also prevented the increase in bone vascular density and bone metastasis triggered by isoproterenol. Together, these results indicate that stimulation of the β2AR in osteoblasts triggers a Vegf-dependent neo-angiogenic switch that promotes bone vascular density and the colonization of the bone microenvironment by metastatic breast cancer cells. © 2017 American Society for Bone and Mineral Research.
© 2017 American Society for Bone and Mineral Research.
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15 MeSH Terms
Heat Shock-Related Protein 20 Peptide Decreases Human Airway Constriction Downstream of β2-Adrenergic Receptor.
Banathy A, Cheung-Flynn J, Goleniewska K, Boyd KL, Newcomb DC, Peebles RS, Komalavilas P
(2016) Am J Respir Cell Mol Biol 55: 225-33
MeSH Terms: Actins, Adrenergic beta-2 Receptor Antagonists, Allergens, Animals, Bronchial Hyperreactivity, Carbachol, Cell Movement, Constriction, HSP20 Heat-Shock Proteins, Humans, Inflammation, Lung, Mice, Muscle Contraction, Muscle Relaxation, Muscle, Smooth, Myocytes, Smooth Muscle, Ovalbumin, Peptides, Receptors, Adrenergic, beta-2, Stress Fibers, Sus scrofa
Show Abstract · Added March 3, 2020
Severe bronchospasm refractory to β-agonists is a challenging aspect of asthma therapy, and novel therapeutics are needed. β-agonist-induced airway smooth muscle (ASM) relaxation is associated with increases in the phosphorylation of the small heat shock-related protein (HSP) 20. We hypothesized that a transducible phosphopeptide mimetic of HSP20 (P20 peptide) causes relaxation of human ASM (HASM) by interacting with target(s) downstream of the β2-adrenergic receptor (β2AR) pathway. The effect of the P20 peptide on ASM contractility was determined in human and porcine ASM using a muscle bath. The effect of the P20 peptide on filamentous actin dynamics and migration was examined in intact porcine ASM and cultured primary HASM cells. The efficacy of the P20 peptide in vivo on airway hyperresponsiveness (AHR) was determined in an ovalbumin (OVA) sensitization and challenge murine model of allergic airway inflammation. P20 peptide caused dose-dependent relaxation of carbachol-precontracted ASM and blocked carbachol-induced contraction. The β2AR inhibitor, (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride (ICI 118,551), abrogated isoproterenol but not P20 peptide-mediated relaxation. The P20 peptide decreased filamentous actin levels in intact ASM, disrupted stress fibers, and inhibited platelet-derived growth factor-induced migration of HASM cells. The P20 peptide treatment reduced methacholine-induced AHR in OVA mice without affecting the inflammatory response. These results suggest that the P20 peptide decreased airway constriction and disrupted stress fibers through regulation of the actin cytoskeleton downstream of β2AR. Thus, the P20 peptide may be a potential therapeutic for asthma refractory to β-agonists.
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MeSH Terms
Stimulation of host bone marrow stromal cells by sympathetic nerves promotes breast cancer bone metastasis in mice.
Campbell JP, Karolak MR, Ma Y, Perrien DS, Masood-Campbell SK, Penner NL, Munoz SA, Zijlstra A, Yang X, Sterling JA, Elefteriou F
(2012) PLoS Biol 10: e1001363
MeSH Terms: Adrenergic beta-Antagonists, Animals, Bone Marrow Cells, Bone Neoplasms, Cell Movement, Female, Mammary Neoplasms, Experimental, Mice, Osteoblasts, Propranolol, Receptors, Adrenergic, beta-2, Signal Transduction, Stromal Cells, Sympathetic Nervous System
Show Abstract · Added November 14, 2013
Bone and lung metastases are responsible for the majority of deaths in patients with breast cancer. Following treatment of the primary cancer, emotional and psychosocial factors within this population precipitate time to recurrence and death, however the underlying mechanism(s) remain unclear. Using a mouse model of bone metastasis, we provide experimental evidence that activation of the sympathetic nervous system, which is one of many pathophysiological consequences of severe stress and depression, promotes MDA-231 breast cancer cell colonization of bone via a neurohormonal effect on the host bone marrow stroma. We demonstrate that induction of RANKL expression in bone marrow osteoblasts, following β2AR stimulation, increases the migration of metastatic MDA-231 cells in vitro, independently of SDF1-CXCR4 signaling. We also show that the stimulatory effect of endogenous (chronic stress) or pharmacologic sympathetic activation on breast cancer bone metastasis in vivo can be blocked with the β-blocker propranolol, and by knockdown of RANK expression in MDA-231 cells. These findings indicate that RANKL promotes breast cancer cell metastasis to bone via its pro-migratory effect on breast cancer cells, independently of its effect on bone turnover. The emerging clinical implication, supported by recent epidemiological studies, is that βAR-blockers and drugs interfering with RANKL signaling, such as Denosumab, could increase patient survival if used as adjuvant therapy to inhibit both the early colonization of bone by metastatic breast cancer cells and the initiation of the "vicious cycle" of bone destruction induced by these cells.
2 Communities
9 Members
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14 MeSH Terms
The effect of arrestin conformation on the recruitment of c-Raf1, MEK1, and ERK1/2 activation.
Coffa S, Breitman M, Hanson SM, Callaway K, Kook S, Dalby KN, Gurevich VV
(2011) PLoS One 6: e28723
MeSH Terms: Animals, Arrestin, Arrestins, COS Cells, Cattle, Chlorocebus aethiops, Embryo, Mammalian, Enzyme Activation, Fibroblasts, HEK293 Cells, Humans, Ligands, MAP Kinase Kinase 1, Mice, Mice, Knockout, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mutant Proteins, Phosphorylation, Protein Binding, Protein Conformation, Proto-Oncogene Proteins c-raf, Receptors, Adrenergic, beta-2, Structure-Activity Relationship, beta-Arrestins
Show Abstract · Added December 10, 2013
Arrestins are multifunctional signaling adaptors originally discovered as proteins that "arrest" G protein activation by G protein-coupled receptors (GPCRs). Recently GPCR complexes with arrestins have been proposed to activate G protein-independent signaling pathways. In particular, arrestin-dependent activation of extracellular signal-regulated kinase 1/2 (ERK1/2) has been demonstrated. Here we have performed in vitro binding assays with pure proteins to demonstrate for the first time that ERK2 directly binds free arrestin-2 and -3, as well as receptor-associated arrestins-1, -2, and -3. In addition, we showed that in COS-7 cells arrestin-2 and -3 association with β(2)-adrenergic receptor (β2AR) significantly enhanced ERK2 binding, but showed little effect on arrestin interactions with the upstream kinases c-Raf1 and MEK1. Arrestins exist in three conformational states: free, receptor-bound, and microtubule-associated. Using conformationally biased arrestin mutants we found that ERK2 preferentially binds two of these: the "constitutively inactive" arrestin-Δ7 mimicking microtubule-bound state and arrestin-3A, a mimic of the receptor-bound conformation. Both rescue arrestin-mediated ERK1/2/activation in arrestin-2/3 double knockout fibroblasts. We also found that arrestin-2-c-Raf1 interaction is enhanced by receptor binding, whereas arrestin-3-c-Raf1 interaction is not.
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1 Members
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25 MeSH Terms
β2-Adrenergic receptor signaling in osteoblasts contributes to the catabolic effect of glucocorticoids on bone.
Ma Y, Nyman JS, Tao H, Moss HH, Yang X, Elefteriou F
(2011) Endocrinology 152: 1412-22
MeSH Terms: Animals, Animals, Newborn, Blotting, Western, Bone and Bones, Cell Differentiation, Cell Line, Cells, Cultured, Cyclic AMP, Dexamethasone, Glucocorticoids, Mice, Osteoblasts, Polymerase Chain Reaction, Prednisolone, Receptors, Adrenergic, beta-2, Signal Transduction, X-Ray Microtomography
Show Abstract · Added November 14, 2013
The sympathetic nervous system is a physiological regulator of bone homeostasis. Autonomic nerves are indeed present in bone, bone cells express the β2-adrenergic receptors (β2AR), and pharmacological or genetic disruption of sympathetic outflow to bone induces bone gain in rodents. These recent findings implied that conditions that affect β2AR signaling in osteoblasts and/or sympathetic drive to bone may contribute to bone diseases. In this study, we show that dexamethasone stimulates the expression of the β2AR in differentiated primary calvarial osteoblasts, as measured by an increase in Adrβ2 mRNA and β2AR protein level after short-term dexamethasone treatment. Isoproterenol-induced cAMP accumulation and the expression of the β2AR target gene Rankl were also significantly increased after dexamethasone pretreatment, indicating that dexamethasone promotes the responsiveness of differentiated osteoblasts to adrenergic stimulation. These in vitro results led to the hypothesis that glucocorticoid-induced bone loss, provoked by increased endogenous or high-dose exogenous glucocorticoids given for the treatment of inflammatory diseases, might, at least in part, be mediated by increased sensitivity of bone-forming cells to the tonic inhibitory effect of sympathetic nerves on bone formation or their stimulatory effect on bone resorption. Supporting this hypothesis, both pharmacological and genetic β2AR blockade in mice significantly reduced the bone catabolic effect of high-dose prednisolone in vivo. This study emphasizes the importance of sympathetic nerves in the regulation of bone homeostasis and indicates that this neuroskeletal signaling axis can be modulated by hormones or drugs and contribute to enhance pathological bone loss.
0 Communities
3 Members
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17 MeSH Terms
Influence of gene-gene interactions on response to albuterol therapy.
Moore PE
(2011) Pharmacogenomics 12: 1-3
MeSH Terms: Albuterol, Asthma, Epistasis, Genetic, Humans, Pharmacogenetics, Polymorphism, Single Nucleotide, Receptors, Adrenergic, beta-2, Signal Transduction, Treatment Outcome
Added May 29, 2014
0 Communities
1 Members
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9 MeSH Terms
beta(2)-adrenergic receptor promoter haplotype influences spirometric response during an acute asthma exacerbation.
Moore PE, Williams SM, Gebretsadik T, Jiang L, Minton PL, Shintani A, Phillips Iii JA, Dawson EP, Hartert TV
(2008) Clin Transl Sci 1: 155-61
MeSH Terms: Acute Disease, Adolescent, Adult, Asthma, Cohort Studies, Demography, Forced Expiratory Volume, Gene Frequency, Haplotypes, Hospitalization, Humans, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Receptors, Adrenergic, beta-2, Spirometry
Show Abstract · Added May 27, 2014
Genetic variants in the beta(2)-adrenergic receptor (ADRB2) coding block have been associated with different parameters of asthma severity, but there is no consensus on which variants are most important. Our objective was to determine whether the genetic variants in the 5'- or 3'-flanking regions of ADRB2 impact the response to therapy. DNA was obtained initially from 72 adults hospitalized for an asthma exacerbation. We sequenced a 5,000 bp region of the ADRB2 gene that spanned the flanking regions and identified 31 single nucleotide polymorphisms (SNPs). Nonresponders to asthma therapy were defined as patients whose forced expiratory volume in 1 second (FEV(1)) worsened by >10% at 24 hours after admission. We then evaluated the relationship between the 19 common SNPs and response to asthma-specific therapy during acute disease exacerbations. Our results showed a significant association between nonresponders and a haplotype of five promoter SNPs in a nearly complete linkage disequilibrium. An analysis of the promoter and coding block polymorphisms in an extended cohort of 99 patients confirmed that promoter haplotype was the genetic component most strongly associated with asthmatic nonresponders, which was statistically significant among whites (p < 0.05). An identification of this promoter haplotype may provide an alternate explanation for the variation in the asthma responses observed with ADRB2 coding block polymorphisms.
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1 Members
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16 MeSH Terms
Genetic variants of GSNOR and ADRB2 influence response to albuterol in African-American children with severe asthma.
Moore PE, Ryckman KK, Williams SM, Patel N, Summar ML, Sheller JR
(2009) Pediatr Pulmonol 44: 649-54
MeSH Terms: Adolescent, African Americans, Albuterol, Aldehyde Oxidoreductases, Asthma, Bronchodilator Agents, Child, Child, Preschool, Drug Resistance, Humans, Linkage Disequilibrium, Pharmacogenetics, Polymorphism, Single Nucleotide, Receptors, Adrenergic, beta-2
Show Abstract · Added May 29, 2014
African Americans are disproportionately affected by asthma. Social and economic factors play a role in this disparity, but there is evidence that genetic factors may also influence the development of asthma and response to therapy in African American children. Our hypothesis is that variations in asthma related genes contribute to the observed asthma disparities by influencing the response to asthma-specific therapy. In order to test this hypothesis, we characterized the clinical response to asthma-specific therapy in 107 African American children who presented to the emergency room in status asthmaticus, with a primary outcome indicator of length of time on continuous albuterol. Single locus analysis indicated that genotype variation in glutathione-dependent S-nitrosoglutathione reductase (GSNOR) is associated with a decreased response to asthma treatment in African American children. A post hoc multi-locus analysis revealed that a combination of four single nucleotide polymorphisms (SNPs) within GSNOR, adrenergic receptor beta 2, and carbamoyl phosphate synthetase-1 give a 70% predictive value for lack of response to therapy. This predictive model needs replication in other cohorts of patients with asthma, but suggests gene-gene interactions may have greater significance than that identified with single variants. Our findings also suggest that genetic variants may contribute to the observed population disparities in asthma.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Exploration of the beta2-adrenergic receptor regulatory regions: the next step in the holy grail of asthma pharmacogenetics research.
Moore PE
(2008) Am J Physiol Lung Cell Mol Physiol 294: L187-9
MeSH Terms: 3' Untranslated Regions, Asthma, Haplotypes, Humans, Pharmacogenetics, Polymorphism, Genetic, RNA Stability, Receptors, Adrenergic, beta-2
Added May 29, 2014
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8 MeSH Terms