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Adrenergic Receptor (adrenergic + receptor)

Distribution by Scientific Domains

Medical Sciences	59%
Life Sciences	34%
Chemistry	4%

Distribution within Medical Sciences

Pharmacology & Pharmaceutical Medicine	27%
Cardiovascular Disease	5%
16 Other Subdomains	63%

Terms modified by Adrenergic Receptor

adrenergic receptor agonist

adrenergic receptor antagonist

adrenergic receptor function

adrenergic receptor gene

Selected Abstracts

The importance of valine 114 in ligand binding in ,2 -adrenergic receptor

PROTEIN SCIENCE, Issue 1 2010
Makoto Arakawa
Abstract G-protein coupled receptors (GPCRs) are transmembrane signaling molecules, with a majority of them performing important physiological roles. ,2 -Adrenergic receptor (,2 -AR) is a well-studied GPCRs that mediates natural responses to the hormones adrenaline and noradrenaline. Analysis of the ligand-binding region of ,2 -AR using the recently solved high-resolution crystal structures revealed a number of highly conserved amino acids that might be involved in ligand binding. However, detailed structure-function studies on some of these residues have not been performed, and their role in ligand binding remains to be elucidated. In this study, we have investigated the structural and functional role of a highly conserved residue valine 114, in hamster ,2 -AR by site-directed mutagenesis. We replaced V114 in hamster ,2 -AR with a number of amino acid residues carrying different functional groups. In addition to the complementary substitutions V114I and V114L, the V114C and V114E mutants also showed significant ligand binding and agonist dependent G-protein activation. However, the V114G, V114T, V114S, and V114W mutants failed to bind ligand in a specific manner. Molecular modeling studies were conducted to interpret these results in structural terms. We propose that the replacement of V114 influences not only the interaction of the ethanolamine side-chains but also the aryl-ring of the ligands tested. Results from this study show that the size and orientation of the hydrophobic residue at position V114 in ,2 -AR affect binding of both agonists and antagonists, but it does not influence the receptor expression or folding. [source]

,-Adrenergic receptors in the nucleus tractus solitarii: fitting a new piece to a complex puzzle

EXPERIMENTAL PHYSIOLOGY, Issue 7 2009
Song T. Yao
No abstract is available for this article. [source]

Environmental risk assessment of human pharmaceuticals in the European Union: A case study with the ,-blocker atenolol

INTEGRATED ENVIRONMENTAL ASSESSMENT AND MANAGEMENT, Issue S1 2010
Anette Küster
Abstract ,-Adrenergic receptor blockers (,-blockers) are applied to treat high blood pressure, ischemic heart disease, and heart rhythm disturbances. Due to their widespread use and limited human metabolism, ,-blockers are widely detected in sewage effluents and surface waters. ,-Adrenergic receptors have been characterized in fish and other aquatic animals, so it can be expected that physiological processes regulated by these receptors in wild animals may be affected by the presence of ,-blockers. Because ecotoxicological data on ,-blockers are scarce, it was decided to choose the ,-blocker atenolol as a case study pharmaceutical within the project ERAPharm. A starting point for the assessment of potential environmental risks was the European guideline on the environmental risk assessment of medicinal products for human use. In Phase I of the risk assessment, the initial predicted environmental concentration (PEC) of atenolol in surface water (500,ng L,1) exceeded the action limit of 10,ng L,1. Thus, a Phase II risk assessment was conducted showing acceptable risks for surface water, for groundwater, and for aquatic microorganisms. Furthermore, atenolol showed a low potential for bioaccumulation as indicated by its low lipophilicity (log KOW,=,0.16), a low potential for exposure of the terrestrial compartment via sludge (log KOC,=,2.17), and a low affinity for sorption to the sediment. Thus, the risk assessment according to Phase II-Tier A did not reveal any unacceptable risk for atenolol. Beyond the requirements of the guideline, additional data on effects and fate were generated within ERAPharm. A 2-generation reproduction test with the waterflea Daphnia magna resulted in the most sensitive no-observed-effect concentration (NOEC) of 1.8,mg L,1. However, even with this NOEC, a risk quotient of 0.003 was calculated, which is still well below the risk threshold limit of 1. Additional studies confirm the outcome of the environmental risk assessment according to EMEA/CHMP (2006). However, atenolol should not be considered as representative for other ,-blockers, such as metoprolol, oxprenolol, and propranolol, some of which show significantly different physicochemical characteristics and varying toxicological profiles in mammalian studies. Integr Environ Assess Manag 2010;6:514,523. © 2009 SETAC [source]

Association of adrenergic receptor gene polymorphisms with different fibromyalgia syndrome domains

ARTHRITIS & RHEUMATISM, Issue 7 2009
Gilberto Vargas-Alarcón
Objective Fibromyalgia (FM) patients have signs of relentless sympathetic hyperactivity associated with hyporeactivity to stress. Adrenergic receptors (ARs) are parts of the sympathetic nervous system that are fundamental for maintenance of homeostasis. We undertook this study to correlate ,-AR and ,-AR gene polymorphisms with the presence of FM and with different domains of the FM syndrome as measured by the Fibromyalgia Impact Questionnaire (FIQ). Methods We studied 78 Mexican FM patients and 48 age-matched controls as well as 78 Spanish FM patients and 71 controls. All subjects studied were women. Single-nucleotide polymorphisms (SNPs) of ,1A -AR (rs574584, rs1383914, rs1048101, and rs573542), ,2 -AR (rs1042713 and rs1042714), and ,3 -AR (rs4994) were analyzed by 5, exonuclease TaqMan polymerase chain reaction. Polymorphic haplotypes were constructed after linkage disequilibrium analysis. Results The ,2 -AR AC haplotype was a risk factor for the presence of FM. This haplotype had an increased frequency in Mexican patients compared with Mexican controls (42.1% versus 30.5%; P = 0.04). Similarly, 50.4% of Spanish patients had this haplotype compared with 40.0% of Spanish controls (P = 0.05). In Spanish patients, the ,1A -AR SNP rs1383914 was associated with the presence of FM (P = 0.01), and the ,1A -AR SNP rs1048101 was linked with FIQ disability (P = 0.02). Mexican patients with the rs574584 GG genotype presented the highest FIQ score compared with Mexican patients with other genotypes (P = 0.01), and in Mexicans SNP rs574584 was associated with FIQ morning stiffness (P = 0.04) and with FIQ tiredness upon awakening (P = 0.02). Conclusion AR gene polymorphisms are related to the risk of developing FM and are also linked to different domains of the FM syndrome. [source]

More PKA independent ,-adrenergic signalling via cAMP: Is Rap1-mediated glucose uptake in vascular smooth cells physiologically important?

BRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2007
J Jensen
The proteome characterising a specific cell type makes up a unique intracellular signalling network and signalling has to be studied in a cell specific manner. ,-Adrenergic receptors are coupled to production of cAMP and PKA was initially believed to be the only protein activated by cAMP. However, cAMP-mediated signalling via Epac and Rap1 has emerged as an important contributor to cAMP signalling. In the current issue of the British Journal of Pharmacology, Kanda and Watanabe report that adrenaline stimulates glucose uptake in vascular smooth muscle cells. With pharmacological methods, supplemented with small interfering RNA against Rap1, the authors demonstrate that adrenaline increases glucose uptake via Gs, adenylate cyclase, cAMP and Rap1 activation. The authors could document neither PKA nor Epac as the receptor for cAMP mediating the effect. Although there is no doubt that Rap1 mediates adrenaline-stimulated glucose uptake in vascular smooth muscle cells, it may be too early to exclude PKA and Epac. British Journal of Pharmacology (2007) 151, 423,425; doi:10.1038/sj.bjp.0707248 [source]

Role of ß Blockers in Congestive Heart Failure

CONGESTIVE HEART FAILURE, Issue 6 2000
MPhil, Nazim Uddin Azam Khan MD
Prolonged activation of the adrenergic nervous system has adverse consequences on the cardiovascular system in patients with congestive heart failure. , adrenergic receptor,blocker therapy modifies these deleterious effects. , blockers have been shown to improve myocardial function and survival when used in conjunction with conventional treatment with diuretics, angiotensinconverting enzyme inhibitors, and digoxin. , blocker therapy in mild-to-moderate heart failure should not be delayed because it causes some reversal of both neurohormonal compensatory mechanisms and the deletorious myocardial remodeling process. This paper reviews the beneficial effects of , adrenergic receptor-blocker therapy on the pathophysiology, symptoms, left ventricular function, morbidity, and mortality in patients with congestive heart failure. [source]

The role of the ,-adrenergic receptor in the leg vasoconstrictor response to orthostatic stress

ACTA PHYSIOLOGICA, Issue 3 2009
M. Kooijman
Abstract Aim:, The prompt increase in peripheral vascular resistance, mediated by sympathetic ,-adrenergic stimulation, is believed to be the key event in blood pressure control during postural stress. However, despite the absence of central sympathetic control of the leg vasculature, postural leg vasoconstriction is preserved in spinal cord-injured individuals (SCI). This study aimed at assessing the contribution of both central and local sympathetically induced ,-adrenergic leg vasoconstriction to head-up tilt (HUT) by including healthy individuals and SCI, who lack central sympathetic baroreflex control over the leg vascular bed. Methods:, In 10 controls and nine SCI the femoral artery was cannulated for drug infusion. Upper leg blood flow (LBF) was measured bilaterally using venous occlusion strain gauge plethysmography before and during 30° HUT throughout intra-arterial infusion of saline or the non-selective ,-adrenergic receptor antagonist phentolamine respectively. Additionally, in six controls the leg vascular response to the cold pressor test was assessed during continued infusion of phentolamine, in order to confirm complete ,-adrenergic blockade by phentolamine. Results:, During infusion of phentolamine HUT still caused vasoconstriction in both groups: leg vascular resistance (mean arterial pressure/LBF) increased by 10 ± 2 AU (compared with 12 ± 2 AU during saline infusion), and 13 ± 3 AU (compared with 7 ± 3 AU during saline infusion) in controls and SCI respectively. Conclusion:, Effective ,-adrenergic blockade did not reduce HUT-induced vasoconstriction, regardless of intact baroreflex control of the leg vasculature. Apparently, redundant mechanisms compensate for the absence of sympathetic ,-adrenoceptor leg vasoconstriction in response to postural stress. [source]

Independent predictive roles of eotaxin Ala23Thr, paraoxonase 2 Ser311Cys and ,3 -adrenergic receptor Trp64Arg polymorphisms on cardiac disease in Type 2 Diabetes,an 8-year prospective cohort analysis of 1297 patients

DIABETIC MEDICINE, Issue 4 2010
Y. Wang
Diabet. Med. 27, 376,383 (2010) Abstract Aims, To examine the independent and joint effects of multiple genetic variants on a cardiac end-point in an 8-year prospective study of a Chinese diabetic cohort. Methods, Seventy-seven single nucleotide polymorphisms (SNPs) of 53 candidate genes for inflammation, thrombosis, vascular tone regulation and lipid metabolism were genotyped in 1297 Chinese patients with no prior history of coronary heart disease (CHD) or heart failure at baseline. Cardiac end-point was defined by the occurrence of CHD and/or heart failure. Results, In Cox regression model, after adjustment for baseline confounding variables including age, sex, smoking status, duration of diabetes, glycaemic control, lipid levels, waist circumference, blood pressure, albuminuria and estimated glomerular filtration rate, genetic variants, including Ala/Ala of SCYA11 (eotaxin) Ala23Thr, Cys/Cys or Cys/Ser of PON2 (paraoxonase 2) Ser311Cys and Arg/Arg of ADRB3 (,3 -adrenergic receptor) Trp64Arg, were independently associated with incident cardiac end-point, with respective hazard ratios (95% confidence interval) of 1.70 (1.10,2.61, P = 0.037), 1.42 (1.08,1.88, P = 0.013) and 3.84 (1.18,12.50, P = 0.025). Analysis of the joint effect of the risk alleles showed significant increased risk of the cardiac end-point with increasing number of risk alleles (P < 0.001). The adjusted risk for the cardiac end-point was 4.11 (P = 0.002) for patients carrying four risk alleles compared with those carrying one or no risk allele. Conclusions, The independent risk conferred by genetic variants encoding pathways such as inflammation and lipid metabolism, not adequately reflected by conventional biomarkers, may identify high-risk individuals for intensified control of modifiable risk factors. [source]

Studies of associations between the Arg389Gly polymorphism of the ,1 -adrenergic receptor gene (ADRB1) and hypertension and obesity in 7677 Danish white subjects

DIABETIC MEDICINE, Issue 4 2007
A. P. Gjesing
Abstract Aims, Activation of the ,1 -adrenergic receptor (ADRB1) causes increased lipolysis in adipose tissue and enhances cardiac output. Analysis of the association of the functional ADRB1 Arg389Gly variant with obesity and hypertension has given ambiguous results. To clarify the potential impact of this variant on obesity and hypertension in the general population, we examined the Arg389Gly variant in a relatively large-scale population-based study. Methods, Case-control studies and quantitative trait analyses were carried out in 7677 Danish Caucasians who were genotyped for the Arg389Gly variant (dbSNP rs1801253) using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Results, A weak association between the Gly allele of the Arg389Gly variant and obesity was observed when comparing cases (n = 1540) defined as body mass index (BMI) > 30 kg/m2 with control subjects (n = 6108) defined as BMI , 30 kg/m2 for both allele frequencies (P = 0.05) and genotype distribution (P = 0.05). Case-control studies (cases n = 2518; control n = 3981) examining the effect on hypertension showed no association with allele frequencies (P = 0.3) or genotype distribution (P = 0.5); however, in the quantitative trait analyses, individuals carrying the Gly allele had slightly but significantly lower diastolic (Arg/Arg = 81.9 mmHg vs. Gly-allele carriers = 81.5 mmHg) and systolic (Arg/Arg = 129.4 mmHg vs. Gly-allele carriers = 128.8 mmHg) blood pressure as well as a lower mean arterial blood pressure. Conclusion, Our results suggest that the Arg389Gly polymorphism does not have any clinically important impact on the pathogenesis of obesity in Danish white subjects. Furthermore, despite the observed minor influence on blood pressure, this variant is most likely not to be a major contributor to the development of hypertension. [source]

Ventricular PKC-, and humoral signaling in DOCA-Salt rats treated with labedipinedilol-A

DRUG DEVELOPMENT RESEARCH, Issue 3 2003
Jwu-Lai Yeh
Abstract Effects of oral antihypertensive monotherapy with labedipinedilol-A, labetalol, atenolol, amlodipine, prazosin (20 mg kg,1 day,1), and short-acting nifedipine (3 mg kg,1 day,1) on DOCA-salt-induced translocation of ventricular protein kinase C-,(PKC-,), humoral signaling, and the cardiovascular system were investigated in rats for 4 weeks. The triple blocking activities of labedipinedilol-A (,/,-adrenoceptor blockade and calcium entry blockade) were compared with single blocking activities of selective drugs. Cytosolic PKC-, immunoreactivity was decreased by labedipinedilol-A, short-acting nifedipine, amlodipine, prazosin, labetalol, atenolol, and losartan. Membranous PKC-, immunoreactivity was significantly decreased by labedipinedilol-A, amlodipine, prazosin, labetalol, and atenolol. Labedipinedilol-A and prazosin more potently decreased membranous than cytosolic PKC-, expression. Labedipinedilol-A, labetalol, and atenolol effectively inhibited DOCA-salt-induced increases in angiotensin II (Ang II). All antihypertensive agents reduced endothelin-1 (ET-1) levels in urine and cardiac weight growth. Treatments with labedipinedilol-A, labetalol, atenolol, and amlodipine normalized DOCA-salt-induced ANP increases. Prazosin did not decrease ANP. Short-acting nifedipine elevated ANP. During long-term antihypertensive therapy in DOCA-salt hypertensive rats, single blockade drugs did not fully inhibit ventricular PKC-, translocation or Ang II, ET-1, and ANP humoral signaling. However, triple blockade labedipinedilol-A therapy had a wide range of ,/,-adrenergic receptor and calcium channel inhibitory activities, including diminished reflux tachycardia, inhibition of PKC-, translocation, and reduction of Ang II, ET-1, and ANP formation. Drug Dev. Res. 59:307,315, 2003. 2003 Wiley-Liss, Inc. [source]

Forearm vasoconstrictor response in uncomplicated type 1 diabetes mellitus

EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 10 2006
P. J. Van Gurp
Abstract Background, According to the ,haemodynamic hypothesis', increased tissue perfusion predisposes to microangiopathy in diabetic patients. We hypothesized that the typical haemodynamic changes underlying the increased tissue perfusion can be explained by a decreased sympathetic nerve activity caused by chronic hyperglycaemia. In this study we investigated sympathetic activity in patients with uncomplicated type 1 diabetes mellitus (DM). Materials and methods, In 15 DM patients (DM duration 6·3 ± 3·8 year; HbA1c 7·9 ± 1·3%) and 16 age- and sex-matched healthy volunteers (Control), sympathetic nervous system activity was measured at rest (baseline) and during sympathoneural stimulation (lower body negative pressure (LBNP)) by means of interstitial and plasma noradrenaline (NA) sampling and power spectral analysis. Muscle sympathetic nerve activity (MSNA) was measured before (baseline) and during a cold pressure test. Forearm blood flow was measured during forearm vascular ,- and ,-adrenergic receptor blockade. Results, At baseline, forearm vascular resistance (FVR), plasma NA concentrations, MSNA and heart rate variability were similar in both groups. LBNP-induced vasoconstriction was significantly attenuated in the DM group compared with the Control group (,FVR: 12 ± 4 vs. 19 ± 3 arbitrary units, P < 0·05). The responses of plasma NA and heart rate variability did not differ. Conclusions,, Baseline FVR and sympathetic nerve activity are normal in patients with uncomplicated type 1 diabetes. However, the forearm vasoconstrictor response to sympathetic stimulation is attenuated, which cannot be attributed to an impaired sympathetic responsiveness. [source]

Phentolamine mesylate relaxes rabbit corpus cavernosum by a nonadrenergic, noncholinergic mechanism

FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2001
Subbarao Vemulapalli
The contribution of NO-cGMP dependent pathway to phentolamine mesylate-evoked nonadrenergic, noncholinergic relaxation of rabbit corpus cavernosum was investigated in vitro. Stimulation of nonadrenergic, noncholinergic neurons of the rabbit corpus cavernosum elicited frequency-related relaxation that was significantly attenuated by L-NAME (NO synthase inhibitor) or ODQ (an inhibitor of guanylate cyclase). Moreover, tetrodotoxin, a sodium channel blocker, abolished the electrical field stimulation-induced relaxation of rabbit corpus cavernosum, suggesting that neuronal release of NO mediates relaxation to electrical field stimulation. Phentolamine mesylate (30 and 100 nM) dose-dependently enhanced electrical field stimulation-induced relaxation of the rabbit corpus cavernosum. Prazosin (30 ,M) and yohimbine (30 ,M) failed to affect phentolamine mesylate-mediated nonadrenergic, noncholinergic rabbit penile smooth muscle relaxation, suggesting that phentolamine relaxes rabbit corpus cavernosum independent of ,-adrenergic receptor blockade. In contrast, pretreatment of the rabbit cavernosal strips with L-NAME significantly-attenuated electrical field stimulation produced relaxations to phentolamine mesylate, suggesting that phentolamine mesylate relaxes rabbit corpus cavernosum by activating NO synthase. The data suggest that phentolamine mesylate relaxes nonadrenergic noncholinergic neurons of the rabbit corpus cavernosum by activating NO synthase and is independent of ,-adrenergic receptor blockade. [source]

Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced pulmonary adenocarcinomas in Syrian golden hamsters contain beta 2-adrenergic receptor single-nucleotide polymorphisms

GENES, CHROMOSOMES AND CANCER, Issue 2 2005
Thomas Masi
Cigarette smoking contributes to the development of lung cancer throughout the world, with cases of pulmonary adenocarcinoma (PAC) the most numerous. Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which is formed from nicotine, has been demonstrated to cause mutations in genes that affect cell regulation and proliferation. Moreover, NNK has been shown to interact directly with and stimulate beta adrenergic receptor (ADRB) signal transduction pathways. Our goal was to determine whether single-nucleotide polymorphisms (SNPs) in the Adrb2 from PAC tumors were induced in golden hamsters by the injection of NNK. Here we report the cloning and sequencing of Adrb2 clones from either dissected lung tumors from NNK-injected animals or whole-lung tissue from water-injected controls. Both sets of animals contained SNPs; however, we found significantly more SNPs in the Adrb2 from NNK-injected animals than in the controls. The majority of these SNPs were novel, nonsynonymous mutations found in regions of the Adrb2 known to be involved in ligand binding, G-protein coupling, and desensitization/down-regulation. Our data verified the mutagenic effects of NNK as well as demonstrated that this animal model provides an outstanding way of identifying mutations not only in the Adrb2, but also in other genes that may play essential roles in the regulation and growth of pulmonary adenocarcinomas. © 2005 Wiley-Liss, Inc. [source]

Levosimendan cardioprotection in acutely ,-1 adrenergic receptor blocked open chest pigs

ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 1 2010
C. METZSCH
Background: Levosimendan and volatile anesthetics have myocardial pre-conditioning effects. ,-1 adrenergic receptor antagonists may inhibit the protective effect of volatile anesthetics. No information exists as to whether this also applies to the pre-conditioning effect of levosimendan. We therefore investigated whether levosimendan added to metoprolol would demonstrate a cardioprotective effect. Methods: Three groups of anesthetized open chest pigs underwent 30 min of myocardial ischemia and 90 min of reperfusion by temporary occlusion of the largest side branch from the circumflex artery or the left anterior descending artery. One group (CTRL) served as a control, in another group (BETA), a metoprolol-loading dose was intravenously injected 30 min before ischemia, and in a third group (BETA+L), a levosimendan infusion was added to metoprolol. Myocardial tissue concentrations of glucose, glycerol, and lactate/pyruvate ratio as the primary end-points were investigated with microdialysis in ischemic and non-ischemic tissues. Results: At the end of the ischemic period, statistically significant differences were only found between CTRL and BETA+L in the ischemic myocardium, with a lower lactate/pyruvate ratio, lower glycerol, and higher glucose concentrations in BETA+L as compared with CTRL. There were no differences in non-ischemic myocardium. From 10 to 90 min of reperfusion, no more differences were found between groups. Conclusion: The cardioprotective effect of levosimendan on ischemic metabolism with a reduction in the myocardial lactate/pyruvate ratio, less glycerol accumulation, and better preserved glucose concentration does not seem to be prevented by ,-1 adrenergic receptor antagonism with metoprolol. [source]

Up-Regulation and Functional Effect of Cardiac ,3 -Adrenoreceptors in Alcoholic Monkeys

ALCOHOLISM, Issue 7 2010
Heng-Jie Cheng
Background:, Recent studies link altered cardiac ,-adrenergic receptor (AR) signaling to the pathology of alcoholic cardiomyopathy (ACM). However, the alteration and functional effect of ,3 -AR activation in ACM are unknown. We tested the hypothesis that chronic alcohol intake causes an up-regulation of cardiac ,3 -AR, which exacerbates myocyte dysfunction and impairs calcium regulation, thereby directly contributing to the progression of ACM. Methods:, We compared myocyte ,3 - and ,1 -AR expression and myocyte contractile ([Ca2+]i), transient ([Ca2+]iT), and Ca2+ current (ICa,L) responses to ,- and ,3 -AR stimulation in myocytes obtained from left ventricle (LV) tissue samples obtained from 10 normal control (C) and 16 monkeys with self-administered alcohol for 12 months prior to necropsy: 6 moderate (M) and 10 heavy (H) drinkers with group average alcohol intakes of 1.5 ± 0.2 and 3.3 ± 0.2 g/kg/d, respectively. Results:, Compared with control myocytes (C), in alcoholic cardiomyocytes, basal cell contraction (dL/dtmax, ,39%, H: 69.8 vs. C: 114.6 ,m/s), relaxation (dR/dtmax, ,37%, 58.2 vs. 92.9 ,m/s), [Ca2+]iT (,34%, 0.23 vs. 0.35), and ICa,L (,25%, 4.8 vs. 6.4pA/pF) were all significantly reduced. Compared with controls, in moderate and heavy drinkers, ,1 -AR protein levels decreased by 23% and 42%, but ,3 -AR protein increased by 46% and 85%, respectively. These changes were associated with altered myocyte functional responses to ,-AR agonist, isoproterenol (ISO), and ,3 -AR agonist, BRL-37344 (BRL). Compared with controls, in alcoholic myocytes, ISO (10,8 M) produced significantly smaller increases in dL/dtmax (H: 40% vs. C: 71%), dR/dtmax (37% vs. 52%), [Ca2+]iT (17% vs. 37%), and ICa,L (17% vs. 27%), but BRL (10,8 M) produced a significantly greater decrease in dL/dtmax (H: ,23% vs. C: ,11%), [Ca2+]iT (,30% vs. ,11%), and ICa,L (,28% vs. ,17%). Conclusions:, Chronic alcohol consumption down-regulates cardiac ,1 - and up-regulates ,3 -ARs, contributing to the abnormal response to catecholamines in ACM. The up-regulation of cardiac ,3 -AR signaling enhances inhibition of LV myocyte contraction and relaxation and exacerbates the dysfunctional [Ca2+]i regulation and, thus, may precede the development of ACM. [source]

,2A -Adrenergic Receptor Signaling Underlies Synergistic Enhancement of Ethanol-Induced Behavioral Impairment by Clonidine

ALCOHOLISM, Issue 3 2009
Tara Summer Bender
Background:, We tested the hypothesis that central ,2A -adrenergic receptor (,2AAR) signaling plays a key role in clonidine-ethanol evoked synergistic behavioral impairment. Methods:, Male Sprague-Dawley rats, with intracisternal and jugular vein cannulae implanted 6 days earlier, were tested for drug-induced behavioral impairment. The latter was assessed as the duration of loss of righting reflex (LORR) and rotorod performance every 15 minutes until the rat recovered to the baseline walk criterion (180 seconds). In a separate cohort, c-Fos expression in locus coeruleus (LC) and cerebellum was determined as a marker of neuronal activity following drug treatment. Results:, Rats that received clonidine (60 ,g/kg, i.v.) followed by ethanol (1 g/kg, i.v.) exhibited synergistic impairment of rotorod performance and LORR. The mixed ,2AAR and I1 -imidazoline receptor agonist clonidine (30, 60, and 90 ,g/kg) synergistically and dose-dependently enhanced behavioral impairment elicited by ethanol (1 g/kg). Possible involvement of I1 -imidazoline receptors was ruled out because selective I1 -agonist rilmenidine (300 ,g/kg, i.v.) did not cause behavioral impairment alone or enhance ethanol-evoked behavioral impairment. Pharmacological blockade of central ,2AAR (RX821002, 0.3 mg i.c.) abolished the synergy between clonidine and ethanol; the behavioral response caused by the drug combination was similar to that caused by ethanol alone. Conversely, involvement of central ,2BAR in the interaction was ruled out because blockade of central ,2BAR (ARC-239) independently evoked a strong sedative effect. Clonidine (60 ,g/kg) or ethanol (1 g/kg) alone increased, but their combination decreased, c-Fos levels in LC, while inconsistent c-Fos responses were observed in cerebellum. Conclusions:, Central ,2AAR, but not I1 -imidazoline or ,2BAR, signaling is implicated in the synergistic enhancement of ethanol-evoked behavioral impairment by clonidine. Although the mechanism of c-Fos response remains to be investigated, this neurochemical response highlights the LC as a neuroanatomical target for clonidine-ethanol behavioral interaction. [source]

Direct Evidence for Imidazoline (I1) Receptor Modulation of Ethanol Action on Norepinephrine-Containing Neurons in the Rostral Ventrolateral Medulla in Conscious Spontaneously Hypertensive Rats

ALCOHOLISM, Issue 4 2007
Guichu Li
Background: Enhancement of the rostral ventrolateral medulla (RVLM) presympathetic (norepinephrine, NE) neuronal activity represents a neurochemical mechanism for the pressor effect of ethanol. In this study, we tested the hypothesis that ethanol action on RVLM presympathetic neurons is selectively influenced by the signaling of the local imidazoline (I1) receptor. To support a neuroanatomical and an I1 -signaling selectivity of ethanol, and to circumvent the confounding effects of anesthesia, the dose-related neurochemical and blood pressure effects of ethanol were investigated in the presence of selective pharmacological interventions that cause reduction in the activity of RVLM or nucleus tractus solitarius (NTS) NE neurons via local activation of the I1 or the ,2 -adrenergic receptor in conscious spontaneously hypertensive rats. Results: Local activation of the I1 receptor by rilmenidine (40 nmol) or by the I1/,2 receptor mixed agonist clonidine (1 nmol), and local activation of the ,2 -adrenergic receptor (,2AR) by the pure ,2AR agonist , -methylnorepinephrine (, -MNE, 10 nmol) caused reductions in RVLM NE, and blood pressure. Intra-RVLM ethanol (1, 5, or 10 ,g), microinjected at the nadir of the neurochemical and hypotensive responses, elicited dose-dependent increments in RVLM NE and blood pressure in the presence of local I1,but not ,2 -receptor activation. Only intra-NTS , -MNE, but not rilmenidine or clonidine, elicited reductions in local NE and blood pressure; ethanol failed to elicit any neurochemical or blood pressure responses in the presence of local activation of the ,2AR within the NTS. Conclusion: The findings support the neuroanatomical selectivity of ethanol, and support the hypothesis that the neurochemical (RVLM NE), and the subsequent cardiovascular, effects of ethanol are selectively modulated by I1 receptor signaling in the RVLM. [source]

(N)-methanocarba-2MeSADP (MRS2365) is a subtype-specific agonist that induces rapid desensitization of the P2Y1 receptor of human platelets

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2006
D. M. BOURDON
Summary., Adenosine diphosphate (ADP) initiates and maintains sustained aggregation of platelets through simultaneous activation of both the Gq -coupled P2Y1 receptor and the Gi -coupled P2Y12 receptor. We recently described the synthesis and P2Y1 receptor-specific agonist activity of (N)-methanocarba-2MeSADP (MRS2365). Consequences of selective activation of the P2Y1 receptor by MRS2365 have been further examined in human platelets. Whereas MRS2365 alone only induced shape change, addition of MRS2365 following epinephrine treatment, which activates the Gi/z -linked, ,2A -adrenergic receptor, resulted in sustained aggregation that was indistinguishable from that observed with ADP. Conversely, the platelet shape change promoted by ADP in the presence of the GPIIb/IIIa antagonist eptifibatide was similar to that promoted by MRS2365. Preaddition of the high affinity P2Y1 receptor antagonist MRS2500 inhibited the effect of MRS2365, whereas addition of MRS2500 subsequent to MRS2365 reversed the MRS2365-induced shape change. Preactivation of the P2Y1 receptor with MRS2365 for 2 min resulted in marked loss of capacity of ADP to induce aggregation as evidenced by a greater than 20-fold rightward shift in the concentration effect curve of ADP. This inhibitory effect of P2Y1 receptor activation was dependent on the concentration of MRS2365 (EC50 = 34 nm). The inhibitory effect of preincubation with MRS2365 was circumvented by activation of the Gq -coupled 5-HT2A receptor suggesting that MRS2365 induces loss of the ADP response as a consequence of desensitization of the Gq -coupled P2Y1 receptor. The time course of MRS2365-induced loss of aggregation response to epinephrine was similar to that observed with ADP. These results further demonstrate the P2Y1 receptor selectivity of MRS2365 and illustrate the occurrence of agonist-induced desensitization of the P2Y1 receptor of human platelets studied in the absence of P2Y12 receptor activation . [source]

Genetics and Asthma Disease Susceptibility in the US Latino Population

MOUNT SINAI JOURNAL OF MEDICINE: A JOURNAL OF PERSONALIZED AND TRANSLATIONAL MEDICINE, Issue 2 2010
Joan Reibman MD
Abstract The US Latino population is heterogeneous with diversity in environmental exposures and socioeconomic status. Moreover, the US Hispanic population derives from numerous countries previously under Spanish rule, and many Hispanics have complex proportions of European, Native American, and African ancestry. Disparities in asthma severity and control are due to complex interactions between environmental exposures, socioeconomic factors, and genetic variations. In addition, diseases within the Latino community may also differ by country of origin. Although US Census data show low asthma rates in the Hispanic population as a whole, there is a lot of variability in the prevalence and morbidity of asthma, with a prevalence of 5.0% in Mexican Americans versus 17.0% in Puerto Ricans. The diversity and population admixture make the study of the genetics of asthma complex in Latino populations. However, an understanding of the genetics of asthma in all populations, including the Latino population, can enhance risk identification, help us to target pharmacological therapy, and guide environmental regulations, all of which can promote a reduction in health disparities. The inclusion of markers of ancestral diversity and the incorporation of techniques to adjust for stratification now make these studies feasible in complex populations, including the Latino population. To date, studies using linkage analyses, genome-wide associations, or candidate gene analyses have identified an association of asthma or asthma-related phenotypes with candidate genes, including interleukin 13, ,-2 adrenergic receptor, a disintegrin and metalloproteinase 33, orosomucoid 1-like 3, and thymic stromal lymphopoietin. As reviewed here, although these genes have been identified in diverse populations, limited studies have been performed in Latino populations, and they have had variable replication. There is a need for the development of registries with well-phenotyped pediatric and adult Latino populations and subgroups for inclusion in the rapidly expanding field of genetic studies, and these studies need to be used to reduce health disparities. Mt Sinai J Med 77:140,148, 2010. © 2010 Mount Sinai School of Medicine [source]

Slow-responders to IV ,2 -adrenergic agonist therapy: Defining a novel phenotype in pediatric asthma,

PEDIATRIC PULMONOLOGY, Issue 7 2008
Christopher L. Carroll MD
Abstract Objectives While aerosolized administration of ,2 -adrenergic receptor (,2 -AR) agonists is the mainstay of treatment for pediatric asthma exacerbations, the efficacy of intravenous (IV) delivery is controversial. Failure to demonstrate improved outcomes with IV ,2 -AR agonists may be due to phenotypic differences within this patient population. Our hypothesis is that children who respond more slowly to IV ,2 -AR agonist therapy comprise a distinct phenotype. Methods Retrospective chart review of all children admitted to the ICU for status asthmaticus who were treated with IV terbutaline between December 2002 and September 2006. Results Seventy-eight children were treated with IV terbutaline according to guidelines that adjusted the dose by clinical asthma score. After examining the histogram of duration of terbutaline infusions, a 48-hr cutoff was chosen to define responsiveness. Thirty-eight (49%) children were slow-responders by this definition. There were no significant differences in baseline asthma severity or severity on admission between the slow-responders and responders. Slow-responders required significantly higher total doses of IV terbutaline, higher maximum administration rates, and had longer ICU and hospital length of stay. Conclusion There were significant differences in outcomes between the responders and slow-responders without differences in acute or chronic illness severity. Other factors may have lead to slower response to IV ,2 -agonist therapy. Pediatr Pulmonol. 2008; 43:627,633. © 2008 Wiley-Liss, Inc. [source]

Variation analysis of ,3 -adrenergic receptor and melanocortin-4 receptor genes in childhood obesity

PEDIATRICS INTERNATIONAL, Issue 2 2007
TOMOE KINOSHITA
Abstract Background: Decreased energy expenditure and increased food intake are principal causes for obesity. In the present study, genotypes of ,3 -adrenergic receptor (,3AR) and of melanocortin-4 receptor (MC4R), both of which are believed to have a close link to the cause of obesity, were analyzed and compared with phenotypes of childhood obesity. Methods: Thirty-five obese children with moderate to severe obesity were enrolled. Direct sequencing of the MC4R coding region and pinpoint-polymerase chain reaction were used to detect genomic variation in the ,3AR gene using peripheral blood-derived DNA. Results: Allele frequency of Trp64Arg variation in the ,3AR gene in the obese subjects was 0.16, which is comparable with that in the healthy general population in eastern Asia. Comparison of phenotypical characteristics did not show a significant difference between Trp/Trp and Trp/Arg subjects. It was notable that body height SD was significantly higher in the Trp/Trp than the Trp/Arg subjects (0.93 ± 1.0 SD vs 0.07 ± 1.3 SD, P= 0.03). Annual weight gains were far beyond a hypothetical fat gain in an Arg64 heterozygote with decreased energy consumption, suggesting increased food intake in childhood obesity. There was, however, no variation in the MC4R gene despite thorough sequencing of the entire coding region. Conclusions: The Trp64Arg variation in the ,3AR gene has no relationship to the degree or the incidence of childhood obesity. The majority of childhood obesity can be characterized as tall stature, more rapid weight gain than that expected by decreased energy expenditure. Further investigation is necessary in regard to the increased food intake as a major cause of childhood obesity. [source]

First Cytoplasmic Loop of Glucagon-like Peptide-1 Receptor Can Function at the Third Cytoplasmic Loop Position of Rhodopsin,

PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 4 2008
Takahiro Yamashita
G protein-coupled receptors (GPCRs) are classified into several families based on their amino acid sequences. In family 1, GPCRs such as rhodopsin and adrenergic receptor, the structure,function relationship has been extensively investigated to demonstrate that exposure of the third cytoplasmic loop is essential for selective G protein activation. In contrast, much less is known about other families. Here we prepared chimeric mutants between Gt-coupled rhodopsin and Gi/Go- and Gs-coupled glucagon-like peptide-1 (GLP-1) receptor of family 2 and tried to identify the loop region that functions at the third cytoplasmic loop position of rhodopsin. We succeeded in expressing a mutant having the first cytoplasmic loop of GLP-1 receptor and found that this mutant activated Gi and Go efficiently but did not activate Gt. Moreover, the rhodopsin mutant having the first loop of Gs-coupled secretin receptor of family 2 decreased the Gi and Go activation efficiencies. Therefore, the first loop of GLP-1 receptor would share a similar role to the third loop of rhodopsin in G protein activation. This result strongly suggested that different families of GPCRs have maintained molecular architectures of their ancestral types to generate a common mechanism, namely exposure of the cytoplasmic loop, to activate peripheral G protein. [source]

The importance of valine 114 in ligand binding in ,2 -adrenergic receptor

Laminin acts via focal adhesion kinase/phosphatidylinositol-3, kinase/protein kinase B to down-regulate ,1 -adrenergic receptor signalling in cat atrial myocytes

THE JOURNAL OF PHYSIOLOGY, Issue 3 2009
Y. G. Wang
We previously reported that short-term (2 h) plating of cat atrial myocytes on the extracellular matrix protein, laminin (LMN) decreases adenylate cyclase activity and ,1 -adrenergic receptor (,1 -AR) stimulation of L-type Ca2+ current (ICa,L). The present study sought to determine whether LMN-mediated down-regulation of ,1 signalling is due to down-regulation of adenylate cyclase and to gain insight into the signalling mechanisms responsible. ,1 -AR stimulation was achieved by 0.01 ,m isoproterenol (isoprenaline) plus 0.1 ,m ICI 118551, a selective ,2 -AR antagonist. Atrial myocytes were plated for at least 2 h on uncoated cover-slips (,LMN) or cover-slips coated with LMN (+LMN). As previously reported, ,1 -AR stimulation of ICa,L was significantly smaller in +LMN compared to ,LMN atrial myocytes. In ,LMN myocytes, 10 ,m LY294002 (LY), a specific inhibitor of PI-(3)K, had no effect on ,1 -AR stimulation of ICa,L. In +LMN myocytes, however, LY significantly increased ,1 -AR stimulation of ICa,L. Western blots revealed that compared with ,LMN myocytes, +LMN myocytes showed a significant increase in Akt phosphorylation at Ser-473, which was prevented by LY. In another approach, +LMN myocytes were infected (multiplicity of infection (MOI), 100; 24 h) with replication-defective adenoviruses (Adv) expressing dominant-negative inhibitors of focal adhesion kinase (FAK) (Adv-FRNK or Adv-Y397F-FAK) or Akt (Adv-dnAkt). Compared with control cells infected with Adv-,-galactosidase, cells infected with Adv-FRNK, Adv-Y397F-FAK or Adv-dnAkt each exhibited a significantly greater ,1 -AR stimulation of ICa,L. In ,LMN myocytes LY had no effect on forskolin (FSK)-stimulated ICa,L. However, in +LMN myocytes LY significantly increased FSK-stimulated ICa,L. Similar results were obtained in +LMN atrial myocytes infected with Adv-FRNK. We conclude that LMN binding to ,1 -integrin receptors acts via FAK/PI-(3)K/Akt to inhibit adenylate cyclase activity and thereby down-regulates ,1 -AR-mediated stimulation of ICa,L. These findings provide new insight into the cellular mechanisms by which the extracellular matrix can modulate atrial ,-AR signalling. [source]

,-Adrenergic and neuropeptide Y Y1 receptor control of collateral circuit conductance: influence of exercise training

THE JOURNAL OF PHYSIOLOGY, Issue 24 2008
Jessica C. Taylor
This study evaluated the role of ,-adrenergic receptor- and neuropeptide Y (NPY) Y1 receptor-mediated vasoconstriction in the collateral circuit of the hind limb. Animals were evaluated either the same day (Acute) or 3 weeks following occlusion of the femoral artery; the 3-week animals were in turn limited to cage activity (Sed) or given daily exercise (Trained). Collateral-dependent blood flows (BFs) were measured during exercise with microspheres before and after ,-receptor inhibition (phentolamine) and then NPY Y1 receptor inhibition (BIBP 3226) at the same running speed. Blood pressures (BPs) were measured above (caudal artery) and below (distal femoral artery) the collateral circuit. Arterial BPs were reduced by ,-inhibition (50,60 mmHg) to ,75 mmHg, but not further by NPY Y1 receptor inhibition. Effective experimental sympatholysis was verified by 50,100% increases (P < 0.001) in conductance of active muscles not affected by femoral occlusion with receptor inhibition. In the absence of receptor inhibition, vascular conductance of the collateral circuit was minimal in the Acute group (0.13 ± 0.02), increased over time in the Sed group (0.41 ± 0.03; P < 0.001), and increased further in the Trained group (0.53 ± 0.03; P < 0.02). Combined receptor inhibition increased collateral circuit conductances (P < 0.005), most in the Acute group (116 ± 37%; P < 0.02), as compared to the Sed (41 ± 6.6%; P < 0.001) and Trained (31 ± 5.6%; P < 0.001) groups. Thus, while the sympathetic influence of the collateral circuit remained in the Sed and Trained animals, it became less influential with time post-occlusion. Collateral conductances were collectively greater (P < 0.01) in the Trained as compared to Sed group, irrespective of the presence or absence of receptor inhibition. Conductances of the active ischaemic calf muscle, with combined receptor inhibition, were suboptimal in the Acute group, but increased in Sed and Trained animals to exceptionally high values (e.g. red fibre section of the gastrocnemius: ,7 ml min,1 (100 g),1 mmHg,1). Thus, occlusion of the femoral artery promulgated vascular adaptations, even in vessels that are not part of the collateral circuit. The presence of active sympathetic control of the collateral circuit, even with exercise training, raises the potential for reductions in collateral BF below that possible by the structure of the collateral circuit. However, even with release of this sympathetic vasoconstriction, conductance of the collateral circuit was significantly greater with exercise training, probably due to the network of structurally larger collateral vessels. [source]

cAMP microdomains and L-type Ca2+ channel regulation in guinea-pig ventricular myocytes

THE JOURNAL OF PHYSIOLOGY, Issue 3 2007
Sunita Warrier
Many different receptors can stimulate cAMP synthesis in the heart, but not all elicit the same functional responses. For example, it has been recognized for some time that prostaglandins such as PGE1 increase cAMP production and activate PKA, but they do not elicit responses like those produced by ,-adrenergic receptor (,AR) agonists such as isoproterenol (isoprenaline), even though both stimulate the same signalling pathway. In the present study, we confirm that isoproterenol, but not PGE1, is able to produce cAMP-dependent stimulation of the L-type Ca2+ current in guinea pig ventricular myocytes. This is despite finding evidence that these cells express EP4 prostaglandin receptors, which are known to activate Gs -dependent signalling pathways. Using fluorescence resonance energy transfer-based biosensors that are either freely diffusible or bound to A kinase anchoring proteins, we demonstrate that the difference is due to the ability of isoproterenol to stimulate cAMP production in cytosolic and caveolar compartments of intact cardiac myocytes, while PGE1 only stimulates cAMP production in the cytosolic compartment. Unlike other receptor-mediated responses, compartmentation of PGE1 responses was not due to concurrent activation of a Gi -dependent signalling pathway or phosphodiesterase activity. Instead, compartmentation of the PGE1 response in cardiac myocytes appears to be due to transient stimulation of cAMP in a microdomain that can communicate directly with the bulk cytosolic compartment but not the caveolar compartment associated with ,AR regulation of L-type Ca2+ channel function. [source]

Reductions in basal limb blood flow and vascular conductance with human ageing: role for augmented ,-adrenergic vasoconstriction

THE JOURNAL OF PHYSIOLOGY, Issue 3 2001
Frank A. Dinenno
1Basal whole-limb blood flow and vascular conductance decrease with age in men. We determined whether these age-associated changes in limb haemodynamics are mediated by tonically augmented sympathetic ,-adrenergic vasoconstriction. 2Seven young (28 ± 2 years; mean ±s.e.m.) and eight older (64 ± 2 years) healthy, normotensive adult men were studied. Baseline femoral artery blood flow (Doppler ultrasound) and calculated vascular conductance were 29 and 31 % lower, respectively, and vascular resistance was 53 % higher in the older men (all P < 0.001). 3Local (intra-femoral artery) ,-adrenergic receptor blockade with phentolamine evoked greater increases in femoral blood flow (105 ± 11 vs. 60 ± 6 %) and vascular conductance (125 ± 13 vs. 66 ± 7 %), and reductions in vascular resistance (55 ± 2 vs. 39 ± 3 %) in the experimental limb of the older compared with the young men (all P < 0.001). As a result, ,-adrenergic receptor blockade eliminated the significance of the age-associated differences in absolute levels of femoral blood flow (500 ± 51 vs. 551 ± 35 ml min,1), vascular conductance (6.02 ± 0.73 vs. 6.33 ± 0.26 U), and vascular resistance (0.17 ± 0.03 vs. 0.16 ± 0.01 U; P= 0.4,0.8, n.s.). Femoral haemodynamics in the control limb were unaffected by phentolamine administration in the contralateral (experimental) limb. Complete ,-adrenergic receptor blockade was demonstrated by the absence of vasoconstriction in the experimental limb in response to the cold pressor test. Local propranolol was administered to control for any ,-adrenergic effects of phentolamine. Propranolol did not affect haemodynamics in the experimental or control limbs. 4Our results indicate that the age-related reductions in basal limb blood flow and vascular conductance are mediated largely by chronically elevated sympathetic ,-adrenergic vasoconstriction. This may have important physiological and pathophysiological implications for the ageing human. [source]

Expression of the porcine adrenergic receptor beta 2 gene in longissimus dorsi muscle is affected by cis -regulatory DNA variation

ANIMAL GENETICS, Issue 1 2009
E. Muráni
Summary The beta-2 adrenergic receptor (AR) mediates metabolic actions of catecholamines, including glycogenolysis, lipolysis and proteolysis, in muscle and adipose tissue. Factors influencing the density of beta-2 ARs thus might affect carcass composition and meat quality. One such factor might represent cis -regulatory DNA variation affecting mRNA expression of the adrenergic receptor beta 2 (ADRB2) gene in relevant tissues. To identify potential cis -regulatory DNA variation of porcine ADRB2, we comparatively sequenced part of the 5, flanking region and identified 10 single nucleotide polymorphisms (SNPs). The SNP at position g.673C>T (AF000134) resides in an evolutionarily conserved region (ECR) in an in silico predicted androgen response element. Quantification of total transcript levels and allelic expression imbalance (AEI) revealed significant variability in mRNA expression of ADRB2 in longissimus dorsi muscle of slaughter pigs, partly attributable to cis -regulatory DNA variation. However, the g.673C>T SNP has, in the given temporo-spatial context, no significant effect but is apparently in linkage disequilibrium with the causal cis -regulatory DNA variant. We used the g.673C>T SNP as a marker to study the association of ADRB2 variation with carcass and meat quality in four commercial lines. We found association with the pH of loin at 45 min and 24 h postmortem (p.m.) and with the pH of ham at 24 h p.m. Supporting evidence for ADRB2 as a candidate gene for pork quality is provided by our assignment of the gene to the telomeric end of the q arm of porcine chromosome 2, where several quantitative trait loci for meat quality were reported. [source]

Adrenergic Receptor Polymorphisms Associated with Resting Heart Rate: The HyperGEN Study

ANNALS OF HUMAN GENETICS, Issue 5 2006
J. B. Wilk
Summary The association between polymorphisms in the ,1, ,2 and ,2B adrenergic receptor (ADR) genes (ADRB1, ADRB2 and ADRA2B) and resting heart rate was examined in white and African-American participants of the HyperGEN Study. All analyses were adjusted for age, sex, body mass index, alcohol use, smoking status and daily exercise within strata of race, hypertension status and beta-blocker use. The Ser49Gly polymorphism of the ,1 ADR was associated with resting heart rate in hypertensive African-Americans and hypertensive whites taking beta-blockers, with carriers of the Gly allele having a higher mean resting heart rate by 2.7 and 4.4 beats per minute (bpm), respectively. The Arg389Gly polymorphism of the ,1 ADR was associated with lower heart rate in the normotensive African-American sample. A ,1 haplotype (Ser49Gly-Arg389Gly) was modestly associated with resting heart rate in the hypertensive African-Americans. The ,2B C/A polymorphism was associated with heart rate in hypertensive whites, and both whites and African-Americans taking beta-blockers, with carriers of the A allele having a higher mean resting heart rate. In summary, each of the ADR gene polymorphisms was associated with heart rate in at least one stratum studied, but there was no consistent association from which one would infer a large genetic contribution to heart rate. [source]

Crystallographic characterization of the PDZ1 domain of the human Na+/H+ exchanger regulatory factor

ACTA CRYSTALLOGRAPHICA SECTION D, Issue 5 2001
Gordon Webster
The Na+/H+ exchanger regulatory factor (NHERF) contains two PDZ domains that mediate the assembly of transmembrane and cytosolic proteins into functional signal transduction complexes. The human NHERF PDZ1 domain, which spans residues 11,99, interacts specifically with carboxy-terminal residues of the ,2 adrenergic receptor and the cystic fibrosis transmembrane conductance regulator. The NHERF PDZ1 was expressed in Escherichia coli as a soluble protein, purified and crystallized in the unbound form using the vapor-diffusion method with 2,M ammonium sulfate as the precipitant. Diffraction data were collected to 1.5,Å resolution using synchrotron radiation. The crystals belong to space group P3121 or P3221, with unit-cell parameters a = b = 51.6, c = 58.9,Å, and one molecule in the asymmetric unit. [source]