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Beta-2 adrenergic receptor diplotype defines a subset of salt-sensitive hypertension.
Pojoga L, Kolatkar NS, Williams JS, Perlstein TS, Jeunemaitre X, Brown NJ, Hopkins PN, Raby BA, Williams GH
(2006) Hypertension 48: 892-900
MeSH Terms: Adolescent, Adult, Aged, Animals, Female, Genetic Variation, Humans, Hypertension, Middle Aged, Phenotype, Polymorphism, Genetic, Rats, Rats, Wistar, Receptors, Adrenergic, beta-2, Sodium Chloride, Dietary
Show Abstract · Added December 10, 2013
Two genetic variants of the beta-2 adrenergic receptor, 46G>A and 79C>G, affect agonist-mediated receptor downregulation and vascular reactivity. We determined whether these variants were associated with hypertension, per se, blood pressure response to dietary sodium, 2 forms of salt-sensitive hypertension (low renin and nonmodulation), and the activity of the renin-angiotensin-aldosterone system. Included are 280 hypertensive and 65 normotensive white subjects who had the 2 beta-2 adrenergic receptor genotypes available. Of all subjects, 171 hypertensive and 48 normotensive subjects had complete data for intermediate phenotyping and blood pressure evaluation on high- and low-sodium balance. The beta-2 adrenergic receptor variants were not associated with hypertension per se. However, among hypertensive subjects, the change (from low to high sodium balance) in mean arterial pressure differed significantly by genotype and by diplotype. Compared with all of the other diplotypes combined, 46AA/79CC was associated with a greater change in blood pressure. Furthermore, this diplotype was associated with low-renin (LR) hypertension (identifying 32% of the LR hypertensives), higher plasma aldosterone, and lower plasma renin and serum potassium levels. In conclusion, the 46AA/79CC diplotype is associated with greater blood pressure response to dietary sodium and higher odds of LR hypertension. We propose that the mechanism for the observed association is inadequate suppression of aldosterone with salt intake, implicating the beta-2 adrenergic receptor in the regulation of aldosterone secretion. This hypothesis was confirmed in isolated glomerulosa cells, where beta-2 adrenergic receptor stimulation increased aldosterone secretion, whereas blockade reduced the stimulated aldosterone response. Importantly, this association could only be detected with an intermediate and not a distant phenotype.
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15 MeSH Terms
Respiratory syncytial virus infection reduces beta2-adrenergic responses in human airway smooth muscle.
Moore PE, Cunningham G, Calder MM, DeMatteo AD, Peeples ME, Summar ML, Peebles RS
(2006) Am J Respir Cell Mol Biol 35: 559-64
MeSH Terms: Adrenergic beta-Agonists, Cells, Cultured, Cyclic AMP, GTP-Binding Protein alpha Subunits, Gi-Go, Haplotypes, Humans, Infant, Isoproterenol, Muscle, Smooth, Receptors, Adrenergic, beta-2, Recombinant Fusion Proteins, Respiratory Syncytial Virus Infections, Respiratory Syncytial Virus, Human, Trachea
Show Abstract · Added May 29, 2014
Although respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract illness in infants, the effect of RSV on human airway smooth muscle (HASM) has not been studied. We hypothesized that RSV has direct effects on cAMP formation and beta(2)-adrenergic receptor (ADRB2) density and that ADRB2 haplotype influences this response. A recombinant green-fluorescent protein (rg) expressing RSV was used to determine whether RSV could infect cultured HASM. Influence of RSV infection on beta(2)-adrenergic responsiveness was determined by measuring differences in isoproterenol (ISO)-induced cyclic AMP (cAMP) formation, ADRB2 density, and G(i) expression in HASM cells challenged with RSV, with ultraviolet-inactivated RSV, and with mock infection. The rgRSV efficiently infected cultured HASM cells. ISO-induced cAMP formation was significantly reduced in cells infected with RSV, compared with mock-infected and ultraviolet-inactivated RSV, in a time- and concentration-dependent manner. Forskolin-induced cAMP formation and Gi expression were not altered in cells infected with RSV, suggesting that the influence of RSV on beta(2)-adrenergic relaxation was upstream of cAMP formation. ADRB2 density was reduced in cells infected with RSV, compared with mock infection, and the Arg16Gln27 ADRB2 haplotype was associated with decreased ISO-induced cAMP formation (P < 0.05) and with decreased ADRB2 density at baseline (P < 0.05). The implications of these results are that limitations of beta(2)-agonists in the treatment of any airway obstruction associated with RSV infection may be related to direct effects of RSV on HASM, and ADRB2 genotype may predict beta(2)-adrenergic responses.
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14 MeSH Terms
Beta2-adrenoceptor genotype and function affect hemodynamic profile heterogeneity in postural tachycardia syndrome.
Jacob G, Garland EM, Costa F, Stein CM, Xie HG, Robertson RM, Biaggioni I, Robertson D
(2006) Hypertension 47: 421-7
MeSH Terms: Adrenergic beta-Agonists, Adult, Arteries, Catecholamines, Codon, Dose-Response Relationship, Drug, Female, Genotype, Glutamic Acid, Glycine, Hemodynamics, Humans, Isoproterenol, Male, Middle Aged, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Posture, Receptors, Adrenergic, beta-2, Syndrome, Tachycardia, Vasodilation
Show Abstract · Added December 10, 2013
Previous studies suggest that the beta2-adrenoceptor functions abnormally in patients with postural tachycardia syndrome (POTS) and may contribute to their altered hemodynamic profile. To test the hypothesis that the beta2-adrenoceptor response is decreased in POTS, we studied: (1) the arterial vasodilation response to the beta agonist, isoproterenol, and (2) the distribution of common polymorphisms (codons 16 and 27) of the gene coding the receptor (beta2-AR) in a large population with POTS. We measured plasma catecholamines and monitored hemodynamics and changes in forearm and leg blood flow to incremental doses of intraarterial isoproterenol in 9 patients with POTS compared with 8 healthy subjects. For polymorphism assessment we collected DNA from 57 patients with POTS and compared with 67 age-sex matched healthy subjects. Circulating catecholamines were significantly higher in POTS subjects compared with controls. Intrabrachial and intrafemoral isoproterenol infusion elicited a dose-dependent increase in blood flow. In healthy subjects, blood flow increased (mean+/-SEM) 400+/-70% in the forearm and 170+/-40% in the leg, but only 280+/-60% in forearms and 120+/-20% in legs of patients with POTS (ANOVA for both P<0.001). The genotype and allele distributions for codons 16 and 27 beta2-AR variants were not different in the 2 groups. However, the blood pressure and plasma norepinephrine levels diverged in patients according to their genotype. Patients with Gly16Gly and patients with Glu27Glu had lower plasma catecholamines and higher supine and upright blood pressure, compared with other genotypes. Therefore, both decreased beta2-adrenoceptor-related vasodilation and beta2-AR polymorphisms may contribute to the hemodynamic diversity of patients with POTS.
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22 MeSH Terms
Leptin regulation of bone resorption by the sympathetic nervous system and CART.
Elefteriou F, Ahn JD, Takeda S, Starbuck M, Yang X, Liu X, Kondo H, Richards WG, Bannon TW, Noda M, Clement K, Vaisse C, Karsenty G
(2005) Nature 434: 514-20
MeSH Terms: Activating Transcription Factor 4, Amino Acid Sequence, Animals, Bone Resorption, Carrier Proteins, Cell Line, Child, Child, Preschool, Cyclic AMP-Dependent Protein Kinases, Gene Deletion, Humans, Leptin, Male, Membrane Glycoproteins, Mice, Models, Neurological, Neoplasm Proteins, Nerve Tissue Proteins, Osteoblasts, Osteogenesis, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B, Receptor, Melanocortin, Type 4, Receptors, Adrenergic, beta-2, Receptors, Leptin, Response Elements, Signal Transduction, Sympathetic Nervous System, Transcription Factors
Show Abstract · Added November 14, 2013
Bone remodelling, the mechanism by which vertebrates regulate bone mass, comprises two phases, namely resorption by osteoclasts and formation by osteoblasts; osteoblasts are multifunctional cells also controlling osteoclast differentiation. Sympathetic signalling via beta2-adrenergic receptors (Adrb2) present on osteoblasts controls bone formation downstream of leptin. Here we show, by analysing Adrb2-deficient mice, that the sympathetic nervous system favours bone resorption by increasing expression in osteoblast progenitor cells of the osteoclast differentiation factor Rankl. This sympathetic function requires phosphorylation (by protein kinase A) of ATF4, a cell-specific CREB-related transcription factor essential for osteoblast differentiation and function. That bone resorption cannot increase in gonadectomized Adrb2-deficient mice highlights the biological importance of this regulation, but also contrasts sharply with the increase in bone resorption characterizing another hypogonadic mouse with low sympathetic tone, the ob/ob mouse. This discrepancy is explained, in part, by the fact that CART ('cocaine amphetamine regulated transcript'), a neuropeptide whose expression is controlled by leptin and nearly abolished in ob/ob mice, inhibits bone resorption by modulating Rankl expression. Our study establishes that leptin-regulated neural pathways control both aspects of bone remodelling, and demonstrates that integrity of sympathetic signalling is necessary for the increase in bone resorption caused by gonadal failure.
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29 MeSH Terms
Beta2-adrenoceptor Thr164Ile polymorphism is associated with markedly decreased vasodilator and increased vasoconstrictor sensitivity in vivo.
Dishy V, Landau R, Sofowora GG, Xie HG, Smiley RM, Kim RB, Byrne DW, Wood AJ, Stein CM
(2004) Pharmacogenetics 14: 517-22
MeSH Terms: Adrenergic alpha-1 Receptor Agonists, Adrenergic beta-2 Receptor Agonists, Adult, Female, Heterozygote, Homozygote, Humans, Isoleucine, Isoproterenol, Phenylephrine, Polymorphism, Genetic, Receptors, Adrenergic, alpha-1, Receptors, Adrenergic, beta-2, Threonine, Vasoconstriction, Vasoconstrictor Agents, Vasodilation, Vasodilator Agents, Veins
Show Abstract · Added December 10, 2013
BACKGROUND - The uncommon Thr164Ile polymorphism of the beta2-adrenoceptor is associated with profoundly altered responses to agonist in vitro; however its effects on vascular responses in vivo are not known. Altered adrenergic vascular sensitivity may contribute to the decreased survival observed in patients with congestive heart failure carrying the Ile164 allele.
METHODS AND RESULTS - We used the linear variable differential transformer dorsal hand vein technique to compare vasodilation in response to the beta-adrenergic receptor agonist, isoproterenol, and vasoconstriction in response to the alpha-adrenergic receptor agonist, phenylephrine, in healthy homozygous (Thr164/Thr164) (n = 21) and heterozygous Thr164/Ile164 (n = 5) women. The dose of isoproterenol required to achieve 50% venodilation (geometric mean; 95% CI) was significantly higher in women with the Ile164 allele (82.5 ng/min; 17.3-394 ng/min) than those without (15.8 ng/min; 11-25 ng/min; P = 0.004). The maximum response to isoproterenol was not different (102 +/- 1% and 102 +/- 3%, respectively, P = 0.9). The dose of phenylephrine needed to induce 50% venoconstriction was significantly lower in women with the Ile164 allele (151 ng/min; 42-543 ng/min) than those without (540 ng/min; 350-835 ng/min; P = 0.02).
CONCLUSIONS - The Thr164Ile polymorphism of the beta2-adrenergic receptor is associated with a five-fold reduction in sensitivity to beta2 receptor agonist-mediated vasodilation; vasoconstrictor sensitivity is increased. The overall effect of the Thr164Ile polymorphism is to shift the balance of adrenergic vascular tone toward vasoconstriction. This suggests a mechanistic explanation for the clinical observation of decreased survival in patients with congestive heart failure heterozygous for the Thr164Ile polymorphism.
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19 MeSH Terms
Erythrocyte G protein-coupled receptor signaling in malarial infection.
Harrison T, Samuel BU, Akompong T, Hamm H, Mohandas N, Lomasney JW, Haldar K
(2003) Science 301: 1734-6
MeSH Terms: Adrenergic beta-2 Receptor Agonists, Adrenergic beta-2 Receptor Antagonists, Adrenergic beta-Agonists, Adrenergic beta-Antagonists, Alprenolol, Animals, Catecholamines, Cyclic AMP, Erythrocyte Membrane, Erythrocytes, GTP-Binding Protein alpha Subunits, Gs, Humans, Malaria, Membrane Microdomains, Mice, Parasitemia, Peptide Fragments, Plasmodium berghei, Plasmodium falciparum, Propranolol, Purinergic P1 Receptor Agonists, Purinergic P1 Receptor Antagonists, Receptors, Adrenergic, beta-2, Receptors, Purinergic P1, Signal Transduction, Stereoisomerism, Vacuoles
Show Abstract · Added December 10, 2013
Erythrocytic mechanisms involved in malarial infection are poorly understood. We have found that signaling via the erythrocyte beta2-adrenergic receptor and heterotrimeric guanine nucleotide-binding protein (Galphas) regulated the entry of the human malaria parasite Plasmodium falciparum. Agonists that stimulate cyclic adenosine 3',5'-monophosphate production led to an increase in malarial infection that could be blocked by specific receptor antagonists. Moreover, peptides designed to inhibit Galphas protein function reduced parasitemia in P. falciparum cultures in vitro, and beta-antagonists reduced parasitemia of P. berghei infections in an in vivo mouse model. Thus, signaling via the erythrocyte beta2-adrenergic receptor and Galphas may regulate malarial infection across parasite species.
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27 MeSH Terms
Conservation of the phosphate-sensitive elements in the arrestin family of proteins.
Celver J, Vishnivetskiy SA, Chavkin C, Gurevich VV
(2002) J Biol Chem 277: 9043-8
MeSH Terms: Animals, Arrestin, Mutagenesis, Site-Directed, Phosphorylation, Protein Conformation, Receptors, Adrenergic, beta-2, Structure-Activity Relationship, Xenopus
Show Abstract · Added December 10, 2013
Arrestins play a key role in the homologous desensitization of G protein-coupled receptors (GPCRs). These cytosolic proteins selectively bind to the agonist-activated and GPCR kinase-phosphorylated forms of the GPCR, precluding its further interaction with the G protein. Certain mutations in visual arrestin yield "constitutively active" proteins that bind with high affinity to the light-activated form of rhodopsin without requiring phosphorylation. The crystal structure of visual arrestin shows that these activating mutations perturb two groups of intramolecular interactions that keep arrestin in its basal (inactive) state. Here we introduced homologous mutations into arrestin2 and arrestin3 and found that the resulting mutants bind to the beta(2)-adrenoreceptor in vitro in a phosphorylation-independent fashion. The same mutants effectively desensitize both the beta(2)-adrenergic and delta-opioid receptors in the absence of receptor phosphorylation in Xenopus oocytes. Moreover, the arrestin mutants also desensitize the truncated delta-opioid receptor from which the C terminus, containing critical phosphorylation sites, has been removed. Conservation of the phosphate-sensitive hot spots in non-visual arrestins suggests that the overall fold is similar to that of visual arrestin and that the mechanisms whereby receptor-attached phosphates drive arrestin transition into the active binding competent state are conserved throughout the arrestin family of proteins.
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8 MeSH Terms
The effect of common polymorphisms of the beta2-adrenergic receptor on agonist-mediated vascular desensitization.
Dishy V, Sofowora GG, Xie HG, Kim RB, Byrne DW, Stein CM, Wood AJ
(2001) N Engl J Med 345: 1030-5
MeSH Terms: Adrenergic alpha-Agonists, Adrenergic beta-Agonists, Adult, Blood Pressure, Dose-Response Relationship, Drug, Female, Genotype, Humans, Isoproterenol, Male, Phenylephrine, Polymorphism, Genetic, Receptors, Adrenergic, beta-2, Vasoconstrictor Agents, Vasodilation
Show Abstract · Added December 10, 2013
BACKGROUND - With continuous exposure to beta2-adrenergic agonists, vascular tissue becomes desensitized to agonist-mediated vasodilatation. We studied the effects of two common polymorphisms of the beta2-adrenergic receptor, one at codon 16 and one at codon 27, on agonist-mediated vasodilatation and desensitization in the vascular bed.
METHODS - We studied 26 healthy subjects who were selected to represent three genotypes: 7 were homozygous for the alleles encoding Arg16 and Gln27, 8 were homozygous for the alleles encoding Gly16 and Gln27, and 11 were homozygous for the alleles encoding Gly16 and Glu27. Vascular responses were assessed by measuring changes in the diameter of a dorsal hand vein. A dose-response curve of the effect of the beta2-adrenergic-receptor agonist isoproterenol was constructed (dose range, 4 to 480 ng per minute). Desensitization was then induced by a 2-hour continuous infusion of isoproterenol, and venodilatation was measured 30, 60, 90, and 120 minutes after the start of the infusion.
RESULTS - Subjects who were homozygous for Arg16 had almost complete desensitization; venodilatation in response to isoproterenol in this group decreased from a mean (+/-SE) of 44+/-11 percent to 8+/-4 percent (P=0.006). In contrast, subjects who were homozygous for Gly16 did not have significant desensitization, irrespective of the amino acid encoded by codon 27. Subjects who were homozygous for Glu27 had higher maximal venodilatation in response to isoproterenol than those who were homozygous for Gln27 (86+/-13 percent vs. 54+/-8 percent, P=0.03).
CONCLUSIONS - The Arg16 polymorphism of the beta2-adrenergic receptor is associated with enhanced agonist-mediated desensitization in the vasculature, and the Glu27 polymorphism is associated with increased agonist-mediated responsiveness. Therefore, polymorphisms of the beta2-adrenergic receptor are potentially important determinants of the vascular response to stress.
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15 MeSH Terms
Role of adenosine in asthma.
Feoktistov I, Biaggioni I
(1996) Drug Dev Res 39: 333-6
MeSH Terms: Adenosine, Adrenergic beta-Antagonists, Animals, Anti-Asthmatic Agents, Asthma, Bronchoconstriction, Bronchodilator Agents, Dogs, Humans, Lung, Mast Cells, Mice, Rats, Receptors, Adrenergic, alpha-2, Receptors, Adrenergic, beta-2, Theophylline, Xanthines
Show Abstract · Added December 10, 2013
Several lines of evidence support the hypothesis that adenosine contributes to asthma. Inhaled adenosine provokes bronchoconstriction in asthmatics, but not in nonasthmatics. This process appears to be mediated by mast cell activation, because it can be blocked by antihistamines and inhibitors of mast cell activation. Inhaled adenosine evokes release of mast cell mediators in bronchoalveolar lavage fluid, including histamine, prostaglandin D2, and tryptase, a specific mast cell marker. Also, adenosine potentiates the immunological activation of mast cells in vitro, including rat peritoneal mast cells, mouse bone marrow-derived mast cells, human lung mast cells, and the human mast cell line HMC-1. The receptor subtype that mediates this activation differs between mast cell type, but preliminary evidence suggests that human lung mast cells express A2B receptors. An argument against the contribution of adenosine in asthma has been the "enprofylline paradox." This xanthine (3-(n-propylyl)xanthine) is as effective an antiasthmatic as theophylline (1,3-dimethyl xanthine) but was initially thought not to be an adenosine receptor antagonist. More recent evidence has confirmed that enprofylline blocks A2B receptors with a Ki (7 microM) similar to that of theophylline (13 microM) and well within its therapeutic plasma levels (5-25 microM). This finding, we believe, resolves the enprofylline paradox and supports the hypothesis that adenosine, through A2B receptor activation, contributes to asthma. Preliminary evidence suggests that A2B receptors are indeed present in human lung mast cells. A2B receptors, therefore, may be a potential target for the development of antiasthmatic drugs.
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17 MeSH Terms
Increased beta-adrenergic responsiveness induced by 14 days exposure to simulated microgravity.
Convertino VA, Polet JL, Engelke KA, Hoffler GW, Lane LD, Blomqvist CG
(1995) J Gravit Physiol 2: P66-7
MeSH Terms: Adrenergic alpha-Agonists, Adrenergic beta-Agonists, Adult, Dose-Response Relationship, Drug, Head-Down Tilt, Heart Rate, Humans, Isoproterenol, Leg, Male, Norepinephrine, Phenylephrine, Receptors, Adrenergic, alpha-1, Receptors, Adrenergic, beta-1, Receptors, Adrenergic, beta-2, Vascular Resistance, Weightlessness Simulation
Show Abstract · Added May 20, 2014
Increased sensitivity of end-organ responses to neuroendocrine stimuli as a result of prolonged exposure to the relative inactivity of microgravity has recently been hypothesized. This notion is based on the inverse relationship between circulating norepinephrine and beta-adrenoreceptor sensitivity. Beta-adrenoreceptor activity is reduced in individuals who have elevated plasma norepinephrine as as a result of regular exposure to upright posture and physical exercise. In contrast, adrenoreceptor hypersensitivity has been reported in patients with dysautonomias in which circulating catecholamines are absent or reduced. Taken together, these studies and the observation that circulating plasma norepinephrine has been reduced during spaceflight and in groundbased simulations of microgravity prompt the suggestion that adrenoreceptor hypersensitivity may be a consequence of the adaptation to spaceflight. We conducted an experiment designed to measure cardiovascular responses to adrenoreceptor agonists in human subjects before and after prolonged exposure to 6 degrees head-down tilt (HDT) to test the hypothesis that adaptation to microgravity increases adrenoreceptor responsiveness, and that this adaptation is associated with reduced levels of circulating norepinephrine.
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17 MeSH Terms