Adrenergic Receptor Function
Published by Anonymous on 2007/9/30 (4426 reads)
1: Trends Endocrinol Metab. 2006 Sep;17(7):269-75. Epub 2006 Jul 21.
Adrenergic receptor polymorphisms and autonomic nervous system function in human obesity.
Yasuda K, Matsunaga T, Adachi T, Aoki N, Tsujimoto G, Tsuda K.
Laboratory of Metabolism, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto, and Diabetic Center, Tsunashimakai-Kosei Hospital, Himeji, Japan. yasuda2@tom.life.h.kyoto-u.ac.jp
Adrenergic receptors (ARs) are cell-surface G-protein-coupled receptors for catecholamines. They are essential components of the sympathetic nervous system, organized within the autonomic nervous system (ANS), which controls various physiological functions, including energy homeostasis and metabolism of glucose and lipids. An impairment of ANS function in metabolism is considered to be one of the pathological states associated with human obesity and related metabolic diseases; thus, alterations in AR function might be implicated in the pathophysiology of these diseases. Several studies have suggested an association between obesity phenotypes and some AR polymorphisms. In vitro and human clinical studies indicate that some of these polymorphisms have functional and pathophysiological significance, including the linkage to ANS function. This review summarizes present knowledge of AR polymorphisms related to human obesity, and their association with ANS function.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16860568 [PubMed - indexed for MEDLINE]
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2: Vascul Pharmacol. 2006 Aug;45(2):77-85. Epub 2006 Jun 27.
Targeted inhibition of phosphoinositide 3-kinase activity as a novel strategy to normalize beta-adrenergic receptor function in heart failure.
Perrino C, Rockman HA, Chiariello M.
Division of Cardiology, University Federico II, Via Pansini 5, Naples, 80131, Italy. perrino@unina.it
Human heart failure is a complex clinical syndrome characterized by extensive abnormalities in the beta-adrenergic receptor (betaAR) system. Normalization of betaAR signalling consistently ameliorates cardiac dysfunction and survival in heart failure, suggesting that betaAR dysfunction may be intrinsically linked to the deterioration of cardiac performance. Agonist-dependent phosphorylation of betaARs by betaAR kinase 1 (betaARK1) initiates the processes of desensitization and downregulation, hallmarks of heart failure. Our recent studies have shown that betaARK1 forms a cytosolic complex with phosphoinositide 3-kinase (PI3K) and that translocation of betaARK1 to the plasma membrane also promotes the betaAR-targeting of PI3Ks. At the plasma membrane, the generation of 3'-phosphorylated phosphatidylinositols by PI3K is required in the process of endocytosis, a prodrome to receptor downregulation. A large body of data now indicates that betaAR-targeting of PI3Ks is consistently associated with abnormalities of betaAR signalling under pathological conditions, including pressure-overload hypertrophy and heart failure from different causes. In this review we will discuss the role of betaAR-targeted PI3K activity and novel experimental strategies to disrupt the betaARK1/PI3K complex and in turn ameliorate betaAR dysfunction and the progression of heart failure.
Publication Types:
Review
PMID: 16807128 [PubMed - indexed for MEDLINE]
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3: Panminerva Med. 2005 Sep;47(3):143-55.
Defects in cardiomyocyte function: role of beta-adrenergic receptor dysfunction.
Perrino C, Esposito G, Rockman HA.
Department of Medicine, Cell Biology and Molecular Genetics, Duke University Medical Center, Durham, NC, USA.
Heart failure is a common clinical syndrome characterized by increased levels of circulating catecholamines and extensive abnormalities in the beta-adrenergic receptor (betaAR) system. Interestingly, whether dampening of betaAR signals is beneficial or detrimental for the failing cardiomyocyte is still controversial. In this review we will discuss a number of studies addressing the role of betaAR dysfunction in the development and progression of cardiomyocyte failure, and novel possible strategies to ameliorate cardiomyocyte contractility in heart failure through the normalization of betaAR signaling.
Publication Types:
Review
PMID: 16462723 [PubMed - indexed for MEDLINE]
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4: Trends Cardiovasc Med. 2006 Jan;16(1):20-4.
beta(1)-Adrenergic receptor function, autoimmunity, and pathogenesis of dilated cardiomyopathy.
Jahns R, Boivin V, Lohse MJ.
Department of Internal Medicine, Medizinische Klinik und Poliklinik I, University of Würzburg, D-97080 Würzburg, Germany. jahns_r@klinik.uni-wuerzburg.de
Dilated cardiomyopathy (DCM) is a heart disease characterized by progressive depression of cardiac function and left ventricular dilatation of unknown etiology in the absence of coronary artery disease. Genetic causes and cardiotoxic substances account for about one third of the DCM cases, but the etiology of the remaining 60% to 70% is still unclear. Over the past two decades, evidence has accumulated continuously that functionally active antibodies or autoantibodies targeting cardiac beta(1)-adrenergic receptors (anti-beta(1)-AR antibodies) may play an important role in the initiation and/or clinical course of DCM. Recent experiments in rats indicate that such antibodies can actually cause DCM. This article reviews current knowledge and recent experimental and clinical findings focusing on the role of the beta(1)-adrenergic receptor as a self-antigen in the pathogenesis of DCM.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16387626 [PubMed - indexed for MEDLINE]
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5: J Allergy Clin Immunol. 2006 Jan;117(1):18-24; quiz 25.
Molecular mechanisms of beta(2)-adrenergic receptor function, response, and regulation.
Johnson M.
GlaxoSmithKline Research and Development, Greenford Road, Middlesex UB6 0HE, United Kingdom. malcolm.w.johnson@gsk.com
The human beta(2)-adrenoceptor is a member of the 7-transmembrane family of receptors, encoded by a gene on chromosome 5, and widely distributed in the respiratory tract. Intracellular signaling after beta(2)-adrenoceptor activation is largely affected through cyclic adenosine monophosphate and protein kinase A. Differences in the mechanism of interaction of short- and long-acting beta(2)-agonists and the beta(2)-receptor are reflected in the kinetics of airway smooth muscle relaxation and the onset and duration of bronchodilation in asthmatic patients. beta-Adrenoceptor desensitization associated with prolonged beta(2)-agonist activation differs depending on the cell type and is reflected in different profiles of clinical tolerance to chronic beta(2)-agonist therapy. A number of genetic polymorphisms of the beta(2)-receptor have been described that appear to alter the behavior of the receptor, including the response to beta(2)-agonists. The synergy between the beta(2)-receptor and the glucocorticoid receptor functions has implications for the combined use of beta(2)-agonists and corticosteroids in the treatment of respiratory disease.
Publication Types:
Review
PMID: 16387578 [PubMed - indexed for MEDLINE]
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6: Proc Am Thorac Soc. 2005;2(4):292-6; discussion 311-2.
Molecular mechanisms of beta2-adrenergic receptor function and regulation.
McGraw DW, Liggett SB.
CardioPulmonary Research Center, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0564, Cincinnati, OH 45267-0564, USA.
It is now clear that the beta2-adrenergic receptor continuously oscillates between various conformations in the basal state, and that agonists act to stabilize one or more conformations. It is conceivable that synthetic agonists might be engineered to preferentially confine the receptor to certain conformations deemed clinically important while having a less stabilizing effect on unwanted conformations. In addition, studies of genetically engineered mice have revealed previously unrecognized cross-talk between the beta2-receptor and phospholipase C, such that removal of the primary dilating pathway results in downregulation of constrictive pathways and overactivity of the dilating pathway increases the contractile response. These results indicate a dynamic interaction between beta2-receptor activity and Gq-coupled receptors that constrict the airway. Potentially, then, during chronic beta-agonist therapy, expression of phospholipase C is increased, the functions of Gq-coupled constrictive receptors are enhanced, and there may be an increased tendency for clinical decompensation due to asthma and chronic obstructive pulmonary disease triggers. Antagonists to these receptors might be able to act synergistically with chronic beta-agonists to block the effect of phospholipase C. Alternatively, perhaps novel phospholipase C antagonists would provide the most efficacious approach to blocking the physiologic sequelae of cross-talk between the beta2-receptor and phospholipase C.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 16267351 [PubMed - indexed for MEDLINE]
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7: Trends Cardiovasc Med. 2004 Aug;14(6):252-6.
Molecular restoration of beta-adrenergic receptor signaling improves contractile function of failing hearts.
Tevaearai HT, Koch WJ.
Clinic for Cardiovascular Surgery, University Hospital, Berne, Switzerland.
beta-adrenergic receptor (betaAR) antagonists, or beta blockers, are now a part of the standard therapeutic arsenal in the medical management of chronic heart failure (HF). Conversely, betaAR stimulation remains the most efficient way to enhance cardiac contractile function acutely, although long-term inotropic therapy based on enhanced betaAR stimulation is likely detrimental. Although altered betaAR signaling plays a pivotal role in the genesis of HF, the choice to therapeutically agonize or antagonize this receptor pathway remains an area of ongoing investigation. Research from the authors' laboratory as well as other research conducted over the last 10 years has produced evidence to support the fact that "normalizing" the betaAR system at a molecular level and improving signaling, instead of blocking it, leads to significant enhancement of cardiac contractile function and prevents ventricular remodeling in HF. This review summarizes the extensive in vivo animal model experimentation that supports the still-controversial hypothesis that increasing the myocardial density of beta(2)-ARs or, more effectively, inhibiting the activity of the betaAR kinase (also referred to as G-protein-coupled receptor kinase 2), represent potential novel therapeutic strategies for HF.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 15451518 [PubMed - indexed for MEDLINE]
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8: Life Sci. 2003 Dec 5;74(2-3):379-89.
Regulation of alpha-1B adrenergic receptor localization, trafficking, function, and stability.
Toews ML, Prinster SC, Schulte NA.
Department of Pharmacology, University of Nebraska Medical Center, 986260 Nebraska Medical Center, Omaha, NE 68198-6260, USA. mtoews@unmc.edu
The alpha-1 adrenergic receptors (alpha(1)ARs) play important roles in normal physiology and in many disease states, and understanding their signaling pathways and regulatory mechanisms is thus of considerable relevance, in particular for identifying pharmacological targets for therapeutic modulation. The expression, function, localization, trafficking, and stability of these receptors are all subject to complex regulation by diverse molecular mechanisms. This article highlights recent studies from our laboratory and others focused on the localization and trafficking of the alpha-1B adrenergic receptor (alpha(1B)AR) subtype and on changes in its stability that are likely to be involved in regulating receptor expression. The role(s) of protein kinase C in alpha(1B)AR sequestration, endocytosis, and extracellular signal-regulated kinase (ERK) activation are summarized, and evidence for alpha(1B)AR localization in caveolae/rafts is presented. Receptor structural domains involved in the multiple steps and mechanisms of agonist-induced desensitization are described. Finally, aspects of alpha(1B)AR structural stability that appear to control its drug-induced up- and down-regulation are discussed. Our understanding of regulation for the alpha(1B)AR subtype provides a model for studies of the differential regulation of the other alpha(1)AR subtypes and may lead to identification of new molecular targets for therapeutic intervention in a variety of disease states.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 14607266 [PubMed - indexed for MEDLINE]
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9: Life Sci. 2002 Sep 27;71(19):2207-15.
Transgenic studies of alpha(1)-adrenergic receptor subtype function.
Tanoue A, Koshimizu TA, Tsujimoto G.
Department of Molecular, Cell Pharmacology, National Center for Child Health and Development Research Institute, Tokyo, Japan.
Mice with altered alpha(1)-adrenergic receptor (AR) genes have become important tools in elucidating the subtype-specific functions of the three alpha(1)-AR subtypes because of the lack of sufficiently subtype-selective pharmacological agents. Mice with a deletion (knockout, KO) or an overexpression (transgenic, TG) of the alpha(1A)-, alpha(1B)-, or alpha(1D)-AR subtypes have been generated. The alpha(1)-ARs are the principal mediators of the hypertensive response to alpha(1)-agonists in the cardiovascular system. Studies with these mice indicate that alpha(1A)-AR and alpha(1B)-AR subtypes play an important role in cardiac development and/or function as well as in blood pressure (BP) response to alpha(1)-agonists via vasoconstriction. The alpha(1B)- and alpha(1D)-subtypes also appear to be involved in central nervous system (CNS) processes such as nociceptive responses, modulation of memory consolidation and working memory. The ability to study subtype-specific functions in different mouse strains by altering the same alpha(1)-AR in different ways strengthens the conclusions drawn from these studies. Although these genetic approaches have limitations, they have significantly increased our understanding of the functions of alpha(1)-AR subtypes.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 12215368 [PubMed - indexed for MEDLINE]
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10: Basic Res Cardiol. 2001 Nov;96(6):528-38.
Presence, distribution and physiological function of adrenergic and muscarinic receptor subtypes in the human heart.
Brodde OE, Bruck H, Leineweber K, Seyfarth T.
Institute of Pharmacology and Toxicology, Martin-Luther-University of Halle-Wittenberg, Halle/Saale, Germany. otto-erich.brodde@medizin.uni-halle.de
The sympathetic and parasympathetic nervous system play a powerful role in controlling cardiac function by activating adrenergic and muscarinic receptors. In the human heart there exist alpha1-, beta1- and beta2-adrenoceptors and M2-muscarinic receptors and possibly also (prejunctional) alpha2-adrenoceptors. Beta1- and beta2-adrenoceptors are quite evenly distributed in the human heart while M2-receptors are heterogeneously distributed (more receptors in atria than in ventricles). Stimulation of beta1- and beta2-adrenoceptors causes increases in heart rate and force of contraction while stimulation of M2-receptors decreases heart rate (directly in atria) and force of contraction (indirectly in ventricles). Pathological situations (such as heart failure) or pharmacological interventions (for example, beta-blocker treatment) can alter the distribution of beta1- and beta2-adrenoceptors in the human heart, while M2-receptors are only marginally affected. On the other hand, relatively little is known on distribution and functional role of alpha1- and alpha2-adrenoceptor subtypes in the human heart.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 11770070 [PubMed - indexed for MEDLINE]
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11: Pharmacol Rev. 2001 Dec;53(4):487-525.
Norepinephrine and beta 2-adrenergic receptor stimulation regulate CD4+ T and B lymphocyte function in vitro and in vivo.
Kohm AP, Sanders VM.
Department of Cell Biology, Neurobiology, and Anatomy, Stritch School of Medicine, Loyola University, Maywood, IL, USA. A-Kohm@Northwestern.edu
Historically, norepinephrine and the sympathetic nervous system have been associated with the "fight or flight" response, and they also contribute to the regulation of autonomic activity within the body, such as cardiovascular function. In addition, evidence over the past 30 years suggests that norepinephrine may also regulate the function of immune cells that protect the body against pathogens. The presence of sympathetic nerve fibers and the release of norepinephrine within lymphoid organs represent a mechanism by which signals from the central nervous system may influence immune cell function. The T cell-dependent antibody response is essential to successful host defense against numerous environmental pathogens. It is during this response that CD4+ T and B lymphocytes are activated to produce cytokines and antibody, respectively, leading to immune competence and protection. The goal of this review is to discuss the evidence supporting the release of norepinephrine within lymphoid organs and the expression of the beta2-adrenergic receptor by CD4+ T and B lymphocytes. We also discuss the mechanisms by which beta2-adrenergic receptor stimulation affects the level of cytokine and antibody produced by these cells both in vitro and in vivo. In cases where conflicting findings have been reported, we discuss potential variables that may have contributed to these conflicting findings. To conclude, we discuss the disease- and health-specific implications of the basic research being done in the area of sympathetic nervous system regulation of T and B lymphocyte function.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 11734616 [PubMed - indexed for MEDLINE]
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12: Rev Physiol Biochem Pharmacol. 2001;142:161-85.
Transgenic models of alpha 2-adrenergic receptor subtype function.
Hein L.
Institut für Pharmakologie und Toxikologie, Universität Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 11190578 [PubMed - indexed for MEDLINE]
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13: Nippon Rinsho. 2000 Feb;58(2):333-7.
[Insulin resistance and beta 3-adrenergic receptor function]
[Article in Japanese]
Kobayashi I, Ishigami T, Umemura S.
Second Department of Internal Medicine, Yokohama City University School of Medicine.
Beta 3-adrenergic receptors are expressed predominantly on white and brown adipocytes. Activation of the receptor stimulates lipolysis in adipose tissues and increases energy expenditure by thermogenesis in brown adipocytes. It is proposed that dysfunction of beta 3-adrenergic receptor result to obesity and insulin resistance. Trp64Arg mutation of human beta 3-adrenergic receptor gene is found frequently in Pima Indians and Japanese, and rare in Caucasians. Although the mutation have little, if any, functional disturbance especially in acute phase in vivo, it is reported to associate to obesity and earlier onset of type 2 diabetes. The role of beta 3-adrenergic receptor in insulin resistance is still unknown in detail. Further studies and clinical applications are expected.
Publication Types:
English Abstract
Review
PMID: 10707554 [PubMed - indexed for MEDLINE]
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14: Methods Mol Biol. 2000;126:241-58.
Antisense RNA/DNA-based techniques to probe adrenergic receptor function.
Wang HY, Lin F, Malbon CC.
Department of Physiology and Biophysics, School of Medicine, State University of New York, Stony Brook, USA.
Publication Types:
Review
PMID: 10685416 [PubMed - indexed for MEDLINE]
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15: J Allergy Clin Immunol. 1999 Aug;104(2 Pt 2):S42-6.
Molecular and genetic basis of beta2-adrenergic receptor function.
Liggett SB.
Departments of Medicine (Pulmonary) and Pharmacology, University of Cincinnati College of Medicine, Ohio, USA.
The beta(2 )-adrenergic receptor has been cloned, mutated, and recombinantly expressed such that many structural features involved in receptor function have been defined. Agonists bind in a pocket formed by transmembrane spanning domains 3, 5, and 6, where key contact points initiate receptor activation. An interaction with the beta-hydroxyl group of beta-agonists and Asn293 of the latter transmembrane domain is the basis of the stereoselectivity of R- vs S-isomers of catecholamine-like agonists. Sites within the receptor that serve to dampen the signal with continuous agonist exposure have also been identified and include sites for phosphorylation by protein kinase A and G-protein-coupled receptor kinases and structural features that direct the receptor toward degradation (downregulation). Several regions of the beta(2 )-adrenergic receptor show genetic diversity within the human population, such that expression, coupling, and agonist regulation may be different in individuals with these polymorphisms.
Publication Types:
Review
PMID: 10452787 [PubMed - indexed for MEDLINE]
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16: J Psychiatr Res. 1999 Jul-Aug;33(4):309-22.
Adrenergic receptor function in panic disorder. II. Neutrophil beta 2 receptors: Gs protein coupling, effects of imipramine treatment and relationship to treatment outcome.
Gurguis GN, Blakeley JE, Antai-Otong D, Vo SP, Orsulak PJ, Petty F, Rush AJ.
Department of Veterans Affairs Medical Center, Laboratory of Clinical Neuroscience, Dallas, TX 75216, USA. gurguis.george@dallas.va.gov
Panic attacks are associated with increased autonomic symptoms, suggesting increased beta 2-adrenergic receptor (beta 2AR) function in PD. Tricyclic antidepressants downregulate beta AR function. Previous studies on beta AR function in PD, however, are inconsistent. We recently found increased beta AR coupling and density in neutrophils of symptomatic drug-free PD patients. This study evaluated beta AR coupling to Gs protein in 28 controls, 25 drug-free PD patients and 8 PD imipramine-treated patients. PD patients had significantly higher coupling and receptor density, particularly in the high-conformational state. Differences were more pronounced in patients with less depressive symptomatology. Treatment with imipramine was associated with decreased beta AR coupling and density in the high-conformational state. Several beta AR binding parameters were related to severity of anxiety symptoms and treatment outcome. Antidepressants downregulate beta AR density and induce uncoupling from Gs protein in PD. Future studies may investigate beta AR coupling in relationship to treatment outcome and the role of beta AR kinase in PD.
Publication Types:
Comparative Study
Research Support, U.S. Gov't, Non-P.H.S.
Review
PMID: 10404469 [PubMed - indexed for MEDLINE]
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17: Adv Exp Med Biol. 1998;437:269-78.
The role of norepinephrine and beta-2-adrenergic receptor stimulation in the modulation of Th1, Th2, and B lymphocyte function.
Sanders VM.
Department of Cell Biology, Nerobiology and Anatomy, Loyola University Medical Center, Maywood, Illinois 60153, USA.
Publication Types:
Review
PMID: 9666280 [PubMed - indexed for MEDLINE]
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18: Masui. 1997 Jul;46(7):934-41.
[Adrenergic receptor and alpha 2 agonist--2: Function analysis of adrenoceptor subtype by knockout mice and knockdown rats]
[Article in Japanese]
Mizobe T.
Department of Anesthesiology, Kyoto Prefectural, University of Medicine.
Alpha 2 adrenergic agonists will soon be used in the anesthetic management for their sedative/hypnotic, anesthetic-sparing, analgesic and sympatholytic properties. But the clinically available alpha 2 agonists have unwanted side-effects such as acute hypertension and bradycardia following a bolus injection because these agonists do not discriminate between the 3 alpha 2 adrenoceptor subtypes. Molecular biological methods can identify mediating receptor subtype for each response. Knockout mice study reveals that the alpha 2 B adrenoceptor subtype mediates the hypertensive response to alpha 2 agonists. Knockdown study using the antisense technology demonstrates that the alpha 2 A adrenoceptor subtype mediates the hypnotic and analgesic effects of alpha 2 agonists. The next generation of alpha 2 agonists should be alpha 2 A selective to maximize anesthetic and analgesic effects while minimizing hypertensive response.
Publication Types:
English Abstract
Review
PMID: 9251508 [PubMed - indexed for MEDLINE]
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19: Masui. 1997 Jun;46(6):770-6.
[Adrenergic receptor and alpha 2 agonist--2: Structure-function relationship of adrenoceptors]
[Article in Japanese]
Mizobe T.
Department of Anesthesiology, Kyoto Prefectural University of Medicine.
Recombinant DNA experiments using chimeric receptors containing portions of alpha 2 and beta 2 adrenoceptors demonstrated structure-function relationships of adrenoceptors. The seventh transmembrane domain determines the subtype ligand binding specificity between alpha 2 and beta 2 adrenoceptors. A further investigation by mutagenesis suggests that a direct interaction between subtype specific ligands and specific amino acids such as Phe (412) and Asn (312) in the seventh transmembrane domain of the alpha 2 and beta 2 adrenoceptors respectively. The third cytoplasmic loop is responsible for determining the specificity of interactions between the receptor and G protein. Recombinant DNA technology also demonstrated that seven transmembrane domains of adrenoceptors have a counterclockwise arrangement when viewed from the outside of the cell.
Publication Types:
English Abstract
Review
PMID: 9223879 [PubMed - indexed for MEDLINE]
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20: Am J Physiol. 1997 Apr;272(4 Pt 2):H1553-9.
Cardiac function in genetically engineered mice with altered adrenergic receptor signaling.
Rockman HA, Koch WJ, Lefkowitz RJ.
Department of Medicine, University of California at San Diego, La Jolla 92093, USA.
In disease states such as heart failure, catecholamines released from sympathetic nerve endings and the adrenal medulla play a central role in the adaptive and maladaptive physiological response to altered tissue perfusion. G protein-coupled receptors are importantly involved in myocardial growth and the regulation of contractility. The adrenergic receptors themselves are regulated by a set of specific kinases, termed the G protein-coupled receptor kinases. The study of complex systems in vivo has recently been advanced by the development of transgenic and gene-targeted "knockout" mouse models. Combining transgenic technology with sophisticated physiological measurements of cardiac function is an extremely powerful strategy for studying the regulation of myocardial contractility in normal animals and in models of disease states. The purpose of this review is to summarize current knowledge about the regulation of cardiovascular homeostasis involving signaling pathways through stimulation of adrenergic receptors.
Publication Types:
Review
PMID: 9139936 [PubMed - indexed for MEDLINE]
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21: Annu Rev Pharmacol Toxicol. 1997;37:421-50.
Structure and function of the beta 3-adrenergic receptor.
Strosberg AD.
Institut Cochin de Génétique Moléculaire, Laboratoire d'Immuno-Pharmacologie Moléculaire, CNRS UPR 0415, Paris, France.
The beta 3 subtype of adrenaline and noradrenaline receptors has now been extensively characterized at the structural and functional levels. Ligand binding and adenylyl cyclase activation studies helped define a beta-adrenergic profile that is quite distinct from that of the beta 1- and beta 2-adrenergic receptors, but strongly reminiscent of most of the "atypical" responses reported in earlier pharmacologic studies. Human, other large mammal, and rodent receptors share most of the characteristic beta 3 properties, although obvious species-specific differences have been identified. Recently, the incidence of a naturally occurring variant of the human beta 3-adrenergic receptor was shown to be correlated with hereditary obesity in Pima Indians and in Japanese individuals, and in Western obese patients with increased dynamic capacity to add on weight and develop non-insulin-dependent diabetes mellitus (NIDDM). A mild weight increase was also shown to develop in female, but not male, mice in which the beta 3 receptor gene was disrupted. Taken together, these results now provide a consistent picture of an important role of the beta 3-adrenoceptor in the regulation of lipid metabolism and as an obvious target for drugs to treat some forms of obesity.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9131260 [PubMed - indexed for MEDLINE]
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22: Circ Res. 1996 May;78(5):737-49.
alpha 1-adrenergic receptor subtypes. Molecular structure, function, and signaling.
Graham RM, Perez DM, Hwa J, Piascik MT.
Victor Chang Cardiac Research Institute, St Vincent's Hospital, Sydney, Australia.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 8620593 [PubMed - indexed for MEDLINE]
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23: Mol Cell Biochem. 1995 Aug-Sep;149-150:217-21.
Membrane phospholipids and adrenergic receptor function.
Williams S, Meij JT, Panagia V.
Division of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada.
We have reviewed the effects on adrenergic receptors by membrane phospholipid alterations secondary to oxidative stress and phospholipases' activity. Experimental evidences indicate that the function of both alpha- and beta-adrenoceptors is regulated by their phospholipid microdomain; however, the underlying mechanism is still undefined. No information seems to be available on the influence of phospholipids on alpha 2-adrenoceptors and on all adrenoceptors' subtypes. Thus, further studies are necessary to clarify the role of membrane phospholipids in regulating the function of each member of the adrenergic receptor superfamily.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 8569732 [PubMed - indexed for MEDLINE]
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24: Am J Cardiol. 1993 Mar 25;71(9):23C-29C.
beta-adrenergic receptor regulation and left ventricular function in idiopathic dilated cardiomyopathy.
Gilbert EM, Olsen SL, Renlund DG, Bristow MR.
Division of Cardiology, University of Utah School of Medicine, Salt Lake City 84132.
Alterations in the myocardial receptor-G protein-adenylate cyclase (RGC) complex and cardiac adrenergic neurons in the failing human heart result in subsensitivity to beta-adrenergic stimulation. Pharmacologic interventions such as beta blockade may modify critical components of the RGC complex and partially restore the sensitivity of the beta-adrenergic pathway. Among the receptors coupled to the stimulatory (Gs) protein are the beta 1 and beta 2 receptors. Because of differences in receptor population and agonist (i.e., norepinephrine) affinity, the beta 1-receptor is the predominate adrenergic subtype regulating contractility in the nonfailing myocardium. Down-regulation occurs in the myocardial beta-receptor component of the RGC complex with mild-to-moderate and severe left ventricular dysfunction. However, abnormalities of the RGC complex vary with the etiology of heart failure; beta 1-receptor down-regulation is greater in idiopathic dilated cardiomyopathy than in post-infarction cardiomyopathy, while beta-receptor uncoupling is greater in post-infarction disease. In chronic heart failure, the adrenergic nervous system is activated in the heart and kidney. There is evidence that an increased cardiac norepinephrine concentration contributes to the decrease in beta 1-receptor density in heart failure. However, norepinephrine exposure is not the only factor responsible for regulating beta-adrenergic receptors in heart failure. Chronic beta blockade may improve hemodynamic and clinical response in patients with idiopathic dilated cardiomyopathy by protecting the myocardium from the cardiotoxic effects of increased catecholamines and by up-regulating the beta 1 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Publication Types:
Review
PMID: 8096672 [PubMed - indexed for MEDLINE]
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25: Annu Rev Pharmacol Toxicol. 1992;32:167-83.
Mutagenesis of the beta 2-adrenergic receptor: how structure elucidates function.
Ostrowski J, Kjelsberg MA, Caron MG, Lefkowitz RJ.
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 1318669 [PubMed - indexed for MEDLINE]
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26: Am J Clin Nutr. 1992 Jan;55(1 Suppl):228S-236S.
Adrenergic receptor function in fat cells.
Arner P.
Department of Medicine, Huddinge Hospital, Karolinska Institute, Stockholm.
All classical adrenoceptor subtypes are functionally expressed in fat cells. However, only beta 1 adrenoceptors appear to be present in all types of fat cells. There is a substantial adrenoceptor reserve in fat cells; approximately 50% of beta and alpha 2 adrenoceptors are spare receptors. Beta adrenoceptors are subject to intensive regulation. They are regulated by insulin, estrogens, and androgens as well as by thyroid hormones and are altered by nutritional factors, diabetes, autonomic neuropathy, and beta-blocking treatment. Alpha receptors are less sensitive to changes except during infancy, when there are marked developmental alterations in the function of alpha 2 adrenoceptors, and during fasting, when there is a decrease in receptor expression. In addition, beta adrenoceptors but not alpha 2 adrenoceptors are sensitive to homologous desensitization after exposure to agonists. Site variations in the expression and function of beta and alpha 2 adrenoceptors, which in part are situated at the level of gene transcription, may be involved in the development of regional obesity.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 1309480 [PubMed - indexed for MEDLINE]
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27: Biochim Biophys Acta. 1991 Oct 26;1095(2):127-39.
Molecular biology of alpha-adrenergic receptors: implications for receptor classification and for structure-function relationships.
Lomasney JW, Cotecchia S, Lefkowitz RJ, Caron MG.
Department of Pathology, Howard Hughes Medical Institute, Duke University Medical Center, Durham 27710.
Publication Types:
Review
PMID: 1657194 [PubMed - indexed for MEDLINE]
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28: Adv Exp Med Biol. 1991;308:223-38.
Structure and function of the adrenergic receptor family.
Roth NS, Lefkowitz RJ, Caron MG.
Howard Hughes Medical Institute, Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710.
Publication Types:
Review
PMID: 1801586 [PubMed - indexed for MEDLINE]
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29: FASEB J. 1990 Aug;4(11):2881-9.
Erratum in:
FASEB J 1990 Sep;4(12):3049.
Turning off the signal: desensitization of beta-adrenergic receptor function.
Hausdorff WP, Caron MG, Lefkowitz RJ.
Howard Hughes Medical Institute, Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710.
Cellular responses to many hormones and neurotransmitters wane rapidly despite continuous exposure of cells to these stimuli. This phenomenon, termed desensitization, has been particularly well studied for the stimulation of cAMP levels by plasma membrane beta-adrenergic receptors (beta AR). The molecular mechanisms underlying rapid beta AR desensitization do not appear to require internalization of the receptors, but rather an alteration in the functioning of beta AR themselves that uncouples the receptors from the stimulatory G protein Gs. This uncoupling phenomenon involves phosphorylation of beta AR by at least two kinases, PKA and the beta AR kinase (beta ARK), which are activated under different desensitizing conditions. Receptor phosphorylation by the two kinases leads to desensitization of the receptor response via distinct biochemical mechanisms, and additional cytosolic factors appear to be involved in the case of beta ARK. Numerous experimental approaches have been used recently to elucidate the molecular details of this ubiquitous biological process.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 2165947 [PubMed - indexed for MEDLINE]
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30: Am Rev Respir Dis. 1990 Feb;141(2 Pt 2):S22-30.
Beta-adrenergic receptors. Relationship of primary structure, receptor function, and regulation.
Fraser CM, Venter JC.
Section of Receptor Biochemistry, National Institute of Neurological and Communicative Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
Publication Types:
Review
PMID: 2155553 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
31: Neurobiol Aging. 1988 Jan-Feb;9(1):53-8.
Alpha- and beta-adrenergic receptor function in the brain during senescence.
Scarpace PJ, Abrass IB.
Geriatric Research, Education and Clinical Center, Sepulveda VA Medical Center, CA 91343.
Alpha- and beta-adrenergic receptors and their second messengers play an important role in brain neurotransmission. Changes in receptor function with age may be involved in the age-related changes in arousal, mood and memory. The predominance of data indicates there is decreased beta-adrenergic receptors in all areas of the brain with the exception of the cortex. Evidence suggests a decreased rate of receptor synthesis may be contributing to this loss of receptors with age. Alpha-adrenergic receptor synthesis is also diminished with age. The modulation of receptor concentrations by hormonal factors is impaired with age, especially the time to recover from receptor down-regulation.
Publication Types:
Review
PMID: 2837671 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
32: Kidney Int Suppl. 1987 Dec;23:S2-13.
Structure and function of the beta 2-adrenergic receptor--homology with rhodopsin.
Dohlman HG, Caron MG, Lefkowitz RJ.
Howard Hughes Medical Institute, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 2831423 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
33: Curr Top Cell Regul. 1986;28:209-31.
Regulation of adrenergic receptor function by phosphorylation.
Lefkowitz RJ, Caron MG.
Mounting evidence suggests that the physiological function of the various subtypes of adrenergic receptors is controlled by phosphorylation/dephosphorylation reactions. It seems intuitively unlikely that this phenomenon will be limited simply to the adrenergic receptors, since these receptors share transmembrane signaling pathways with a host of other plasma membrane receptors. Different types of kinases appear to be involved. On the one hand, phosphorylation reactions may operate in a classical feedback regulatory sense. Thus, the cAMP-dependent protein kinase, once activated by a beta-agonist, can feedback-regulate the function of the receptors by phosphorylating and desensitizing them. Similarly, protein kinase C appears to be able to feedback-regulate the function of alpha 1-adrenergic receptors by phosphorylation. There may also be "cross talk" between the systems. Thus, protein kinase C, when stimulated by phorbols, is able to phosphorylate and desensitize the beta-adrenergic receptors. Moreover, very recently we have found that the cAMP-dependent protein kinase can phosphorylate the alpha 1-adrenergic receptors in vitro. These are examples of one transmembrane signaling system regulating the function of another. Perhaps most interestingly, it appears that there may be a previously unappreciated class of receptor kinases in the cytosol of cells. The first of these, which we have recently found and named beta-ARK, serves to phosphorylate only the agonist-occupied form of the beta-adrenergic receptor. As noted, it is somewhat analogous to the rhodopsin kinase. Such highly specific receptor kinases, which can phosphorylate only the agonist-occupied form of a receptor, represent a potentially elegant mechanism for controlling the function of receptors in a fashion which is linked to their physiological stimulation. How widespread such kinases are, and the actual roles which they play in regulating receptor function, remain to be determined. Finally, it should be stressed that although this review has focused on the regulatory role of receptor phosphorylation, it is by no means our intent to suggest that receptors are the only locus for physiological control of sensitivity to hormone and drug reaction. There is already evidence that guanine nucleotide regulatory proteins can be regulated, and it seems likely that each of the components of the system, including the adenylate cyclase, are likely to be involved in various forms of complex regulation. To date, however, the receptors represent that component of the system whose regulation we understand in the greatest detail.
Publication Types:
Review
PMID: 3024910 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
34: J Am Geriatr Soc. 1985 Mar;33(3):184-8.
The impact of aging on adrenergic receptor function: clinical and biochemical aspects.
Heinsimer JA, Lefkowitz RJ.
From this discussion, several conclusions can be drawn. First, with advancing age there is a decrease in cardiovascular responsiveness and, more specifically, there is a decrease in catecholamine-stimulated chronotropic and inotropic responses. This decreased function has its biochemical correlate in the observation that cyclic AMP levels are decreased in response to isoproterenol infusion in cells or tissues derived from aged organisms. Second, although most work on human circulating cells suggests that beta-adrenergic receptor densities are unchanged, measurements of beta-adrenergic receptor concentrations in various cells from various animals (predominantly rats) have yielded conflicting results. Some of this disparity could be due to the observation that local concentrations of norepinephrine, such as those found intramyocardially, may be very different from those in circulating plasma. Indeed, whereas circulating norepinephrine levels tend to rise with age, the intramyocardial norepinephrine levels tend to fall with senescence. Thus, circulating lymphocytes may or may not be an appropriate model to reflect the catecholamine milieu to which other tissues may be exposed. Accordingly, a note of caution must be entered in terms of extrapolating findings regarding the levels of human lymphocyte beta-adrenergic receptors and cyclic AMP activity to those found, for example, in the human heart. Furthermore, it is likely that age-related changes in adrenergic function may be the result of changes in coupling of receptors to the adenylate cyclase system, as suggested by Feldman and co-workers, and/or changes in steps distal to cyclase activation, as suggested by Guarnieri and colleagues.(ABSTRACT TRUNCATED AT 250 WORDS)
Publication Types:
In Vitro
Review
PMID: 2857740 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
35: Mol Cell Endocrinol. 1984 Oct;37(3):245-56.
Receptor-specific mechanisms of desensitization of beta-adrenergic receptor function.
Hertel C, Perkins JP.
beta-Adrenergic receptor (beta AR)-specific, agonist-induced desensitization of adenylate cyclase can be shown in most mammalian cells examined to involve at least three reactions. An initial 'uncoupling' reaction leads to a 40-60% loss of catecholamine-stimulated adenylate cyclase activity at a time when no detectable loss of beta AR has occurred. This process precedes by 45-90 sec the appearance of beta AR in cytoplasmic vesicles. Such beta AR exhibit ligand binding properties consistent with their existence on the inside of membrane vesicles; thus, they appear to be formed by a process of agonist-induced beta AR internalization (endocytosis). A third process results in the loss of beta AR, at least in some cases due to receptor degradation. In general, agonist-induced desensitization or down-regulation reactions do not require protein synthesis. Recovery from the desensitized states does not require protein synthesis, whereas recovery from beta AR down-regulation (degraded receptors) requires new receptor synthesis. Agonist-induced beta AR desensitization and down-regulation reactions appear to have much in common with the process of polypeptide hormone-induced receptor down-regulation. The availability of a large number of ligands (agonists, partial agonists and antagonists) for the beta AR should allow the use of this receptor system to gain unique insights into the general processes of ligand-induced, cell surface receptor endocytosis.
Publication Types:
Review
PMID: 6094283 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
36: Nippon Rinsho. 1975 Jul 10;33(7):2254-63.
[Contractile function of the heart. Adrenergic beta receptor blockaders and cardiac function]
[Article in Japanese]
Ito M, Kanaya S, Mashiba H.
Publication Types:
Review
PMID: 523 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
37: Drugs. 1974;7(1):130-8.
Adverse effects of beta-adrenergic receptor blocking drugs on respiratory function.
Beumer HM.
Publication Types:
Comparative Study
Review
PMID: 4151697 [PubMed - indexed for MEDLINE]
Adrenergic receptor polymorphisms and autonomic nervous system function in human obesity.
Yasuda K, Matsunaga T, Adachi T, Aoki N, Tsujimoto G, Tsuda K.
Laboratory of Metabolism, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto, and Diabetic Center, Tsunashimakai-Kosei Hospital, Himeji, Japan. yasuda2@tom.life.h.kyoto-u.ac.jp
Adrenergic receptors (ARs) are cell-surface G-protein-coupled receptors for catecholamines. They are essential components of the sympathetic nervous system, organized within the autonomic nervous system (ANS), which controls various physiological functions, including energy homeostasis and metabolism of glucose and lipids. An impairment of ANS function in metabolism is considered to be one of the pathological states associated with human obesity and related metabolic diseases; thus, alterations in AR function might be implicated in the pathophysiology of these diseases. Several studies have suggested an association between obesity phenotypes and some AR polymorphisms. In vitro and human clinical studies indicate that some of these polymorphisms have functional and pathophysiological significance, including the linkage to ANS function. This review summarizes present knowledge of AR polymorphisms related to human obesity, and their association with ANS function.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16860568 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
2: Vascul Pharmacol. 2006 Aug;45(2):77-85. Epub 2006 Jun 27.
Targeted inhibition of phosphoinositide 3-kinase activity as a novel strategy to normalize beta-adrenergic receptor function in heart failure.
Perrino C, Rockman HA, Chiariello M.
Division of Cardiology, University Federico II, Via Pansini 5, Naples, 80131, Italy. perrino@unina.it
Human heart failure is a complex clinical syndrome characterized by extensive abnormalities in the beta-adrenergic receptor (betaAR) system. Normalization of betaAR signalling consistently ameliorates cardiac dysfunction and survival in heart failure, suggesting that betaAR dysfunction may be intrinsically linked to the deterioration of cardiac performance. Agonist-dependent phosphorylation of betaARs by betaAR kinase 1 (betaARK1) initiates the processes of desensitization and downregulation, hallmarks of heart failure. Our recent studies have shown that betaARK1 forms a cytosolic complex with phosphoinositide 3-kinase (PI3K) and that translocation of betaARK1 to the plasma membrane also promotes the betaAR-targeting of PI3Ks. At the plasma membrane, the generation of 3'-phosphorylated phosphatidylinositols by PI3K is required in the process of endocytosis, a prodrome to receptor downregulation. A large body of data now indicates that betaAR-targeting of PI3Ks is consistently associated with abnormalities of betaAR signalling under pathological conditions, including pressure-overload hypertrophy and heart failure from different causes. In this review we will discuss the role of betaAR-targeted PI3K activity and novel experimental strategies to disrupt the betaARK1/PI3K complex and in turn ameliorate betaAR dysfunction and the progression of heart failure.
Publication Types:
Review
PMID: 16807128 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
3: Panminerva Med. 2005 Sep;47(3):143-55.
Defects in cardiomyocyte function: role of beta-adrenergic receptor dysfunction.
Perrino C, Esposito G, Rockman HA.
Department of Medicine, Cell Biology and Molecular Genetics, Duke University Medical Center, Durham, NC, USA.
Heart failure is a common clinical syndrome characterized by increased levels of circulating catecholamines and extensive abnormalities in the beta-adrenergic receptor (betaAR) system. Interestingly, whether dampening of betaAR signals is beneficial or detrimental for the failing cardiomyocyte is still controversial. In this review we will discuss a number of studies addressing the role of betaAR dysfunction in the development and progression of cardiomyocyte failure, and novel possible strategies to ameliorate cardiomyocyte contractility in heart failure through the normalization of betaAR signaling.
Publication Types:
Review
PMID: 16462723 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
4: Trends Cardiovasc Med. 2006 Jan;16(1):20-4.
beta(1)-Adrenergic receptor function, autoimmunity, and pathogenesis of dilated cardiomyopathy.
Jahns R, Boivin V, Lohse MJ.
Department of Internal Medicine, Medizinische Klinik und Poliklinik I, University of Würzburg, D-97080 Würzburg, Germany. jahns_r@klinik.uni-wuerzburg.de
Dilated cardiomyopathy (DCM) is a heart disease characterized by progressive depression of cardiac function and left ventricular dilatation of unknown etiology in the absence of coronary artery disease. Genetic causes and cardiotoxic substances account for about one third of the DCM cases, but the etiology of the remaining 60% to 70% is still unclear. Over the past two decades, evidence has accumulated continuously that functionally active antibodies or autoantibodies targeting cardiac beta(1)-adrenergic receptors (anti-beta(1)-AR antibodies) may play an important role in the initiation and/or clinical course of DCM. Recent experiments in rats indicate that such antibodies can actually cause DCM. This article reviews current knowledge and recent experimental and clinical findings focusing on the role of the beta(1)-adrenergic receptor as a self-antigen in the pathogenesis of DCM.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16387626 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
5: J Allergy Clin Immunol. 2006 Jan;117(1):18-24; quiz 25.
Molecular mechanisms of beta(2)-adrenergic receptor function, response, and regulation.
Johnson M.
GlaxoSmithKline Research and Development, Greenford Road, Middlesex UB6 0HE, United Kingdom. malcolm.w.johnson@gsk.com
The human beta(2)-adrenoceptor is a member of the 7-transmembrane family of receptors, encoded by a gene on chromosome 5, and widely distributed in the respiratory tract. Intracellular signaling after beta(2)-adrenoceptor activation is largely affected through cyclic adenosine monophosphate and protein kinase A. Differences in the mechanism of interaction of short- and long-acting beta(2)-agonists and the beta(2)-receptor are reflected in the kinetics of airway smooth muscle relaxation and the onset and duration of bronchodilation in asthmatic patients. beta-Adrenoceptor desensitization associated with prolonged beta(2)-agonist activation differs depending on the cell type and is reflected in different profiles of clinical tolerance to chronic beta(2)-agonist therapy. A number of genetic polymorphisms of the beta(2)-receptor have been described that appear to alter the behavior of the receptor, including the response to beta(2)-agonists. The synergy between the beta(2)-receptor and the glucocorticoid receptor functions has implications for the combined use of beta(2)-agonists and corticosteroids in the treatment of respiratory disease.
Publication Types:
Review
PMID: 16387578 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
6: Proc Am Thorac Soc. 2005;2(4):292-6; discussion 311-2.
Molecular mechanisms of beta2-adrenergic receptor function and regulation.
McGraw DW, Liggett SB.
CardioPulmonary Research Center, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0564, Cincinnati, OH 45267-0564, USA.
It is now clear that the beta2-adrenergic receptor continuously oscillates between various conformations in the basal state, and that agonists act to stabilize one or more conformations. It is conceivable that synthetic agonists might be engineered to preferentially confine the receptor to certain conformations deemed clinically important while having a less stabilizing effect on unwanted conformations. In addition, studies of genetically engineered mice have revealed previously unrecognized cross-talk between the beta2-receptor and phospholipase C, such that removal of the primary dilating pathway results in downregulation of constrictive pathways and overactivity of the dilating pathway increases the contractile response. These results indicate a dynamic interaction between beta2-receptor activity and Gq-coupled receptors that constrict the airway. Potentially, then, during chronic beta-agonist therapy, expression of phospholipase C is increased, the functions of Gq-coupled constrictive receptors are enhanced, and there may be an increased tendency for clinical decompensation due to asthma and chronic obstructive pulmonary disease triggers. Antagonists to these receptors might be able to act synergistically with chronic beta-agonists to block the effect of phospholipase C. Alternatively, perhaps novel phospholipase C antagonists would provide the most efficacious approach to blocking the physiologic sequelae of cross-talk between the beta2-receptor and phospholipase C.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 16267351 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
7: Trends Cardiovasc Med. 2004 Aug;14(6):252-6.
Molecular restoration of beta-adrenergic receptor signaling improves contractile function of failing hearts.
Tevaearai HT, Koch WJ.
Clinic for Cardiovascular Surgery, University Hospital, Berne, Switzerland.
beta-adrenergic receptor (betaAR) antagonists, or beta blockers, are now a part of the standard therapeutic arsenal in the medical management of chronic heart failure (HF). Conversely, betaAR stimulation remains the most efficient way to enhance cardiac contractile function acutely, although long-term inotropic therapy based on enhanced betaAR stimulation is likely detrimental. Although altered betaAR signaling plays a pivotal role in the genesis of HF, the choice to therapeutically agonize or antagonize this receptor pathway remains an area of ongoing investigation. Research from the authors' laboratory as well as other research conducted over the last 10 years has produced evidence to support the fact that "normalizing" the betaAR system at a molecular level and improving signaling, instead of blocking it, leads to significant enhancement of cardiac contractile function and prevents ventricular remodeling in HF. This review summarizes the extensive in vivo animal model experimentation that supports the still-controversial hypothesis that increasing the myocardial density of beta(2)-ARs or, more effectively, inhibiting the activity of the betaAR kinase (also referred to as G-protein-coupled receptor kinase 2), represent potential novel therapeutic strategies for HF.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 15451518 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
8: Life Sci. 2003 Dec 5;74(2-3):379-89.
Regulation of alpha-1B adrenergic receptor localization, trafficking, function, and stability.
Toews ML, Prinster SC, Schulte NA.
Department of Pharmacology, University of Nebraska Medical Center, 986260 Nebraska Medical Center, Omaha, NE 68198-6260, USA. mtoews@unmc.edu
The alpha-1 adrenergic receptors (alpha(1)ARs) play important roles in normal physiology and in many disease states, and understanding their signaling pathways and regulatory mechanisms is thus of considerable relevance, in particular for identifying pharmacological targets for therapeutic modulation. The expression, function, localization, trafficking, and stability of these receptors are all subject to complex regulation by diverse molecular mechanisms. This article highlights recent studies from our laboratory and others focused on the localization and trafficking of the alpha-1B adrenergic receptor (alpha(1B)AR) subtype and on changes in its stability that are likely to be involved in regulating receptor expression. The role(s) of protein kinase C in alpha(1B)AR sequestration, endocytosis, and extracellular signal-regulated kinase (ERK) activation are summarized, and evidence for alpha(1B)AR localization in caveolae/rafts is presented. Receptor structural domains involved in the multiple steps and mechanisms of agonist-induced desensitization are described. Finally, aspects of alpha(1B)AR structural stability that appear to control its drug-induced up- and down-regulation are discussed. Our understanding of regulation for the alpha(1B)AR subtype provides a model for studies of the differential regulation of the other alpha(1)AR subtypes and may lead to identification of new molecular targets for therapeutic intervention in a variety of disease states.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 14607266 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
9: Life Sci. 2002 Sep 27;71(19):2207-15.
Transgenic studies of alpha(1)-adrenergic receptor subtype function.
Tanoue A, Koshimizu TA, Tsujimoto G.
Department of Molecular, Cell Pharmacology, National Center for Child Health and Development Research Institute, Tokyo, Japan.
Mice with altered alpha(1)-adrenergic receptor (AR) genes have become important tools in elucidating the subtype-specific functions of the three alpha(1)-AR subtypes because of the lack of sufficiently subtype-selective pharmacological agents. Mice with a deletion (knockout, KO) or an overexpression (transgenic, TG) of the alpha(1A)-, alpha(1B)-, or alpha(1D)-AR subtypes have been generated. The alpha(1)-ARs are the principal mediators of the hypertensive response to alpha(1)-agonists in the cardiovascular system. Studies with these mice indicate that alpha(1A)-AR and alpha(1B)-AR subtypes play an important role in cardiac development and/or function as well as in blood pressure (BP) response to alpha(1)-agonists via vasoconstriction. The alpha(1B)- and alpha(1D)-subtypes also appear to be involved in central nervous system (CNS) processes such as nociceptive responses, modulation of memory consolidation and working memory. The ability to study subtype-specific functions in different mouse strains by altering the same alpha(1)-AR in different ways strengthens the conclusions drawn from these studies. Although these genetic approaches have limitations, they have significantly increased our understanding of the functions of alpha(1)-AR subtypes.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 12215368 [PubMed - indexed for MEDLINE]
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10: Basic Res Cardiol. 2001 Nov;96(6):528-38.
Presence, distribution and physiological function of adrenergic and muscarinic receptor subtypes in the human heart.
Brodde OE, Bruck H, Leineweber K, Seyfarth T.
Institute of Pharmacology and Toxicology, Martin-Luther-University of Halle-Wittenberg, Halle/Saale, Germany. otto-erich.brodde@medizin.uni-halle.de
The sympathetic and parasympathetic nervous system play a powerful role in controlling cardiac function by activating adrenergic and muscarinic receptors. In the human heart there exist alpha1-, beta1- and beta2-adrenoceptors and M2-muscarinic receptors and possibly also (prejunctional) alpha2-adrenoceptors. Beta1- and beta2-adrenoceptors are quite evenly distributed in the human heart while M2-receptors are heterogeneously distributed (more receptors in atria than in ventricles). Stimulation of beta1- and beta2-adrenoceptors causes increases in heart rate and force of contraction while stimulation of M2-receptors decreases heart rate (directly in atria) and force of contraction (indirectly in ventricles). Pathological situations (such as heart failure) or pharmacological interventions (for example, beta-blocker treatment) can alter the distribution of beta1- and beta2-adrenoceptors in the human heart, while M2-receptors are only marginally affected. On the other hand, relatively little is known on distribution and functional role of alpha1- and alpha2-adrenoceptor subtypes in the human heart.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 11770070 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
11: Pharmacol Rev. 2001 Dec;53(4):487-525.
Norepinephrine and beta 2-adrenergic receptor stimulation regulate CD4+ T and B lymphocyte function in vitro and in vivo.
Kohm AP, Sanders VM.
Department of Cell Biology, Neurobiology, and Anatomy, Stritch School of Medicine, Loyola University, Maywood, IL, USA. A-Kohm@Northwestern.edu
Historically, norepinephrine and the sympathetic nervous system have been associated with the "fight or flight" response, and they also contribute to the regulation of autonomic activity within the body, such as cardiovascular function. In addition, evidence over the past 30 years suggests that norepinephrine may also regulate the function of immune cells that protect the body against pathogens. The presence of sympathetic nerve fibers and the release of norepinephrine within lymphoid organs represent a mechanism by which signals from the central nervous system may influence immune cell function. The T cell-dependent antibody response is essential to successful host defense against numerous environmental pathogens. It is during this response that CD4+ T and B lymphocytes are activated to produce cytokines and antibody, respectively, leading to immune competence and protection. The goal of this review is to discuss the evidence supporting the release of norepinephrine within lymphoid organs and the expression of the beta2-adrenergic receptor by CD4+ T and B lymphocytes. We also discuss the mechanisms by which beta2-adrenergic receptor stimulation affects the level of cytokine and antibody produced by these cells both in vitro and in vivo. In cases where conflicting findings have been reported, we discuss potential variables that may have contributed to these conflicting findings. To conclude, we discuss the disease- and health-specific implications of the basic research being done in the area of sympathetic nervous system regulation of T and B lymphocyte function.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 11734616 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
12: Rev Physiol Biochem Pharmacol. 2001;142:161-85.
Transgenic models of alpha 2-adrenergic receptor subtype function.
Hein L.
Institut für Pharmakologie und Toxikologie, Universität Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 11190578 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
13: Nippon Rinsho. 2000 Feb;58(2):333-7.
[Insulin resistance and beta 3-adrenergic receptor function]
[Article in Japanese]
Kobayashi I, Ishigami T, Umemura S.
Second Department of Internal Medicine, Yokohama City University School of Medicine.
Beta 3-adrenergic receptors are expressed predominantly on white and brown adipocytes. Activation of the receptor stimulates lipolysis in adipose tissues and increases energy expenditure by thermogenesis in brown adipocytes. It is proposed that dysfunction of beta 3-adrenergic receptor result to obesity and insulin resistance. Trp64Arg mutation of human beta 3-adrenergic receptor gene is found frequently in Pima Indians and Japanese, and rare in Caucasians. Although the mutation have little, if any, functional disturbance especially in acute phase in vivo, it is reported to associate to obesity and earlier onset of type 2 diabetes. The role of beta 3-adrenergic receptor in insulin resistance is still unknown in detail. Further studies and clinical applications are expected.
Publication Types:
English Abstract
Review
PMID: 10707554 [PubMed - indexed for MEDLINE]
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14: Methods Mol Biol. 2000;126:241-58.
Antisense RNA/DNA-based techniques to probe adrenergic receptor function.
Wang HY, Lin F, Malbon CC.
Department of Physiology and Biophysics, School of Medicine, State University of New York, Stony Brook, USA.
Publication Types:
Review
PMID: 10685416 [PubMed - indexed for MEDLINE]
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15: J Allergy Clin Immunol. 1999 Aug;104(2 Pt 2):S42-6.
Molecular and genetic basis of beta2-adrenergic receptor function.
Liggett SB.
Departments of Medicine (Pulmonary) and Pharmacology, University of Cincinnati College of Medicine, Ohio, USA.
The beta(2 )-adrenergic receptor has been cloned, mutated, and recombinantly expressed such that many structural features involved in receptor function have been defined. Agonists bind in a pocket formed by transmembrane spanning domains 3, 5, and 6, where key contact points initiate receptor activation. An interaction with the beta-hydroxyl group of beta-agonists and Asn293 of the latter transmembrane domain is the basis of the stereoselectivity of R- vs S-isomers of catecholamine-like agonists. Sites within the receptor that serve to dampen the signal with continuous agonist exposure have also been identified and include sites for phosphorylation by protein kinase A and G-protein-coupled receptor kinases and structural features that direct the receptor toward degradation (downregulation). Several regions of the beta(2 )-adrenergic receptor show genetic diversity within the human population, such that expression, coupling, and agonist regulation may be different in individuals with these polymorphisms.
Publication Types:
Review
PMID: 10452787 [PubMed - indexed for MEDLINE]
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16: J Psychiatr Res. 1999 Jul-Aug;33(4):309-22.
Adrenergic receptor function in panic disorder. II. Neutrophil beta 2 receptors: Gs protein coupling, effects of imipramine treatment and relationship to treatment outcome.
Gurguis GN, Blakeley JE, Antai-Otong D, Vo SP, Orsulak PJ, Petty F, Rush AJ.
Department of Veterans Affairs Medical Center, Laboratory of Clinical Neuroscience, Dallas, TX 75216, USA. gurguis.george@dallas.va.gov
Panic attacks are associated with increased autonomic symptoms, suggesting increased beta 2-adrenergic receptor (beta 2AR) function in PD. Tricyclic antidepressants downregulate beta AR function. Previous studies on beta AR function in PD, however, are inconsistent. We recently found increased beta AR coupling and density in neutrophils of symptomatic drug-free PD patients. This study evaluated beta AR coupling to Gs protein in 28 controls, 25 drug-free PD patients and 8 PD imipramine-treated patients. PD patients had significantly higher coupling and receptor density, particularly in the high-conformational state. Differences were more pronounced in patients with less depressive symptomatology. Treatment with imipramine was associated with decreased beta AR coupling and density in the high-conformational state. Several beta AR binding parameters were related to severity of anxiety symptoms and treatment outcome. Antidepressants downregulate beta AR density and induce uncoupling from Gs protein in PD. Future studies may investigate beta AR coupling in relationship to treatment outcome and the role of beta AR kinase in PD.
Publication Types:
Comparative Study
Research Support, U.S. Gov't, Non-P.H.S.
Review
PMID: 10404469 [PubMed - indexed for MEDLINE]
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17: Adv Exp Med Biol. 1998;437:269-78.
The role of norepinephrine and beta-2-adrenergic receptor stimulation in the modulation of Th1, Th2, and B lymphocyte function.
Sanders VM.
Department of Cell Biology, Nerobiology and Anatomy, Loyola University Medical Center, Maywood, Illinois 60153, USA.
Publication Types:
Review
PMID: 9666280 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
18: Masui. 1997 Jul;46(7):934-41.
[Adrenergic receptor and alpha 2 agonist--2: Function analysis of adrenoceptor subtype by knockout mice and knockdown rats]
[Article in Japanese]
Mizobe T.
Department of Anesthesiology, Kyoto Prefectural, University of Medicine.
Alpha 2 adrenergic agonists will soon be used in the anesthetic management for their sedative/hypnotic, anesthetic-sparing, analgesic and sympatholytic properties. But the clinically available alpha 2 agonists have unwanted side-effects such as acute hypertension and bradycardia following a bolus injection because these agonists do not discriminate between the 3 alpha 2 adrenoceptor subtypes. Molecular biological methods can identify mediating receptor subtype for each response. Knockout mice study reveals that the alpha 2 B adrenoceptor subtype mediates the hypertensive response to alpha 2 agonists. Knockdown study using the antisense technology demonstrates that the alpha 2 A adrenoceptor subtype mediates the hypnotic and analgesic effects of alpha 2 agonists. The next generation of alpha 2 agonists should be alpha 2 A selective to maximize anesthetic and analgesic effects while minimizing hypertensive response.
Publication Types:
English Abstract
Review
PMID: 9251508 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
19: Masui. 1997 Jun;46(6):770-6.
[Adrenergic receptor and alpha 2 agonist--2: Structure-function relationship of adrenoceptors]
[Article in Japanese]
Mizobe T.
Department of Anesthesiology, Kyoto Prefectural University of Medicine.
Recombinant DNA experiments using chimeric receptors containing portions of alpha 2 and beta 2 adrenoceptors demonstrated structure-function relationships of adrenoceptors. The seventh transmembrane domain determines the subtype ligand binding specificity between alpha 2 and beta 2 adrenoceptors. A further investigation by mutagenesis suggests that a direct interaction between subtype specific ligands and specific amino acids such as Phe (412) and Asn (312) in the seventh transmembrane domain of the alpha 2 and beta 2 adrenoceptors respectively. The third cytoplasmic loop is responsible for determining the specificity of interactions between the receptor and G protein. Recombinant DNA technology also demonstrated that seven transmembrane domains of adrenoceptors have a counterclockwise arrangement when viewed from the outside of the cell.
Publication Types:
English Abstract
Review
PMID: 9223879 [PubMed - indexed for MEDLINE]
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20: Am J Physiol. 1997 Apr;272(4 Pt 2):H1553-9.
Cardiac function in genetically engineered mice with altered adrenergic receptor signaling.
Rockman HA, Koch WJ, Lefkowitz RJ.
Department of Medicine, University of California at San Diego, La Jolla 92093, USA.
In disease states such as heart failure, catecholamines released from sympathetic nerve endings and the adrenal medulla play a central role in the adaptive and maladaptive physiological response to altered tissue perfusion. G protein-coupled receptors are importantly involved in myocardial growth and the regulation of contractility. The adrenergic receptors themselves are regulated by a set of specific kinases, termed the G protein-coupled receptor kinases. The study of complex systems in vivo has recently been advanced by the development of transgenic and gene-targeted "knockout" mouse models. Combining transgenic technology with sophisticated physiological measurements of cardiac function is an extremely powerful strategy for studying the regulation of myocardial contractility in normal animals and in models of disease states. The purpose of this review is to summarize current knowledge about the regulation of cardiovascular homeostasis involving signaling pathways through stimulation of adrenergic receptors.
Publication Types:
Review
PMID: 9139936 [PubMed - indexed for MEDLINE]
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21: Annu Rev Pharmacol Toxicol. 1997;37:421-50.
Structure and function of the beta 3-adrenergic receptor.
Strosberg AD.
Institut Cochin de Génétique Moléculaire, Laboratoire d'Immuno-Pharmacologie Moléculaire, CNRS UPR 0415, Paris, France.
The beta 3 subtype of adrenaline and noradrenaline receptors has now been extensively characterized at the structural and functional levels. Ligand binding and adenylyl cyclase activation studies helped define a beta-adrenergic profile that is quite distinct from that of the beta 1- and beta 2-adrenergic receptors, but strongly reminiscent of most of the "atypical" responses reported in earlier pharmacologic studies. Human, other large mammal, and rodent receptors share most of the characteristic beta 3 properties, although obvious species-specific differences have been identified. Recently, the incidence of a naturally occurring variant of the human beta 3-adrenergic receptor was shown to be correlated with hereditary obesity in Pima Indians and in Japanese individuals, and in Western obese patients with increased dynamic capacity to add on weight and develop non-insulin-dependent diabetes mellitus (NIDDM). A mild weight increase was also shown to develop in female, but not male, mice in which the beta 3 receptor gene was disrupted. Taken together, these results now provide a consistent picture of an important role of the beta 3-adrenoceptor in the regulation of lipid metabolism and as an obvious target for drugs to treat some forms of obesity.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9131260 [PubMed - indexed for MEDLINE]
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22: Circ Res. 1996 May;78(5):737-49.
alpha 1-adrenergic receptor subtypes. Molecular structure, function, and signaling.
Graham RM, Perez DM, Hwa J, Piascik MT.
Victor Chang Cardiac Research Institute, St Vincent's Hospital, Sydney, Australia.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 8620593 [PubMed - indexed for MEDLINE]
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23: Mol Cell Biochem. 1995 Aug-Sep;149-150:217-21.
Membrane phospholipids and adrenergic receptor function.
Williams S, Meij JT, Panagia V.
Division of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada.
We have reviewed the effects on adrenergic receptors by membrane phospholipid alterations secondary to oxidative stress and phospholipases' activity. Experimental evidences indicate that the function of both alpha- and beta-adrenoceptors is regulated by their phospholipid microdomain; however, the underlying mechanism is still undefined. No information seems to be available on the influence of phospholipids on alpha 2-adrenoceptors and on all adrenoceptors' subtypes. Thus, further studies are necessary to clarify the role of membrane phospholipids in regulating the function of each member of the adrenergic receptor superfamily.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 8569732 [PubMed - indexed for MEDLINE]
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24: Am J Cardiol. 1993 Mar 25;71(9):23C-29C.
beta-adrenergic receptor regulation and left ventricular function in idiopathic dilated cardiomyopathy.
Gilbert EM, Olsen SL, Renlund DG, Bristow MR.
Division of Cardiology, University of Utah School of Medicine, Salt Lake City 84132.
Alterations in the myocardial receptor-G protein-adenylate cyclase (RGC) complex and cardiac adrenergic neurons in the failing human heart result in subsensitivity to beta-adrenergic stimulation. Pharmacologic interventions such as beta blockade may modify critical components of the RGC complex and partially restore the sensitivity of the beta-adrenergic pathway. Among the receptors coupled to the stimulatory (Gs) protein are the beta 1 and beta 2 receptors. Because of differences in receptor population and agonist (i.e., norepinephrine) affinity, the beta 1-receptor is the predominate adrenergic subtype regulating contractility in the nonfailing myocardium. Down-regulation occurs in the myocardial beta-receptor component of the RGC complex with mild-to-moderate and severe left ventricular dysfunction. However, abnormalities of the RGC complex vary with the etiology of heart failure; beta 1-receptor down-regulation is greater in idiopathic dilated cardiomyopathy than in post-infarction cardiomyopathy, while beta-receptor uncoupling is greater in post-infarction disease. In chronic heart failure, the adrenergic nervous system is activated in the heart and kidney. There is evidence that an increased cardiac norepinephrine concentration contributes to the decrease in beta 1-receptor density in heart failure. However, norepinephrine exposure is not the only factor responsible for regulating beta-adrenergic receptors in heart failure. Chronic beta blockade may improve hemodynamic and clinical response in patients with idiopathic dilated cardiomyopathy by protecting the myocardium from the cardiotoxic effects of increased catecholamines and by up-regulating the beta 1 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Publication Types:
Review
PMID: 8096672 [PubMed - indexed for MEDLINE]
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25: Annu Rev Pharmacol Toxicol. 1992;32:167-83.
Mutagenesis of the beta 2-adrenergic receptor: how structure elucidates function.
Ostrowski J, Kjelsberg MA, Caron MG, Lefkowitz RJ.
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 1318669 [PubMed - indexed for MEDLINE]
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26: Am J Clin Nutr. 1992 Jan;55(1 Suppl):228S-236S.
Adrenergic receptor function in fat cells.
Arner P.
Department of Medicine, Huddinge Hospital, Karolinska Institute, Stockholm.
All classical adrenoceptor subtypes are functionally expressed in fat cells. However, only beta 1 adrenoceptors appear to be present in all types of fat cells. There is a substantial adrenoceptor reserve in fat cells; approximately 50% of beta and alpha 2 adrenoceptors are spare receptors. Beta adrenoceptors are subject to intensive regulation. They are regulated by insulin, estrogens, and androgens as well as by thyroid hormones and are altered by nutritional factors, diabetes, autonomic neuropathy, and beta-blocking treatment. Alpha receptors are less sensitive to changes except during infancy, when there are marked developmental alterations in the function of alpha 2 adrenoceptors, and during fasting, when there is a decrease in receptor expression. In addition, beta adrenoceptors but not alpha 2 adrenoceptors are sensitive to homologous desensitization after exposure to agonists. Site variations in the expression and function of beta and alpha 2 adrenoceptors, which in part are situated at the level of gene transcription, may be involved in the development of regional obesity.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 1309480 [PubMed - indexed for MEDLINE]
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27: Biochim Biophys Acta. 1991 Oct 26;1095(2):127-39.
Molecular biology of alpha-adrenergic receptors: implications for receptor classification and for structure-function relationships.
Lomasney JW, Cotecchia S, Lefkowitz RJ, Caron MG.
Department of Pathology, Howard Hughes Medical Institute, Duke University Medical Center, Durham 27710.
Publication Types:
Review
PMID: 1657194 [PubMed - indexed for MEDLINE]
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28: Adv Exp Med Biol. 1991;308:223-38.
Structure and function of the adrenergic receptor family.
Roth NS, Lefkowitz RJ, Caron MG.
Howard Hughes Medical Institute, Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710.
Publication Types:
Review
PMID: 1801586 [PubMed - indexed for MEDLINE]
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29: FASEB J. 1990 Aug;4(11):2881-9.
Erratum in:
FASEB J 1990 Sep;4(12):3049.
Turning off the signal: desensitization of beta-adrenergic receptor function.
Hausdorff WP, Caron MG, Lefkowitz RJ.
Howard Hughes Medical Institute, Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710.
Cellular responses to many hormones and neurotransmitters wane rapidly despite continuous exposure of cells to these stimuli. This phenomenon, termed desensitization, has been particularly well studied for the stimulation of cAMP levels by plasma membrane beta-adrenergic receptors (beta AR). The molecular mechanisms underlying rapid beta AR desensitization do not appear to require internalization of the receptors, but rather an alteration in the functioning of beta AR themselves that uncouples the receptors from the stimulatory G protein Gs. This uncoupling phenomenon involves phosphorylation of beta AR by at least two kinases, PKA and the beta AR kinase (beta ARK), which are activated under different desensitizing conditions. Receptor phosphorylation by the two kinases leads to desensitization of the receptor response via distinct biochemical mechanisms, and additional cytosolic factors appear to be involved in the case of beta ARK. Numerous experimental approaches have been used recently to elucidate the molecular details of this ubiquitous biological process.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 2165947 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
30: Am Rev Respir Dis. 1990 Feb;141(2 Pt 2):S22-30.
Beta-adrenergic receptors. Relationship of primary structure, receptor function, and regulation.
Fraser CM, Venter JC.
Section of Receptor Biochemistry, National Institute of Neurological and Communicative Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
Publication Types:
Review
PMID: 2155553 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
31: Neurobiol Aging. 1988 Jan-Feb;9(1):53-8.
Alpha- and beta-adrenergic receptor function in the brain during senescence.
Scarpace PJ, Abrass IB.
Geriatric Research, Education and Clinical Center, Sepulveda VA Medical Center, CA 91343.
Alpha- and beta-adrenergic receptors and their second messengers play an important role in brain neurotransmission. Changes in receptor function with age may be involved in the age-related changes in arousal, mood and memory. The predominance of data indicates there is decreased beta-adrenergic receptors in all areas of the brain with the exception of the cortex. Evidence suggests a decreased rate of receptor synthesis may be contributing to this loss of receptors with age. Alpha-adrenergic receptor synthesis is also diminished with age. The modulation of receptor concentrations by hormonal factors is impaired with age, especially the time to recover from receptor down-regulation.
Publication Types:
Review
PMID: 2837671 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
32: Kidney Int Suppl. 1987 Dec;23:S2-13.
Structure and function of the beta 2-adrenergic receptor--homology with rhodopsin.
Dohlman HG, Caron MG, Lefkowitz RJ.
Howard Hughes Medical Institute, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 2831423 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
33: Curr Top Cell Regul. 1986;28:209-31.
Regulation of adrenergic receptor function by phosphorylation.
Lefkowitz RJ, Caron MG.
Mounting evidence suggests that the physiological function of the various subtypes of adrenergic receptors is controlled by phosphorylation/dephosphorylation reactions. It seems intuitively unlikely that this phenomenon will be limited simply to the adrenergic receptors, since these receptors share transmembrane signaling pathways with a host of other plasma membrane receptors. Different types of kinases appear to be involved. On the one hand, phosphorylation reactions may operate in a classical feedback regulatory sense. Thus, the cAMP-dependent protein kinase, once activated by a beta-agonist, can feedback-regulate the function of the receptors by phosphorylating and desensitizing them. Similarly, protein kinase C appears to be able to feedback-regulate the function of alpha 1-adrenergic receptors by phosphorylation. There may also be "cross talk" between the systems. Thus, protein kinase C, when stimulated by phorbols, is able to phosphorylate and desensitize the beta-adrenergic receptors. Moreover, very recently we have found that the cAMP-dependent protein kinase can phosphorylate the alpha 1-adrenergic receptors in vitro. These are examples of one transmembrane signaling system regulating the function of another. Perhaps most interestingly, it appears that there may be a previously unappreciated class of receptor kinases in the cytosol of cells. The first of these, which we have recently found and named beta-ARK, serves to phosphorylate only the agonist-occupied form of the beta-adrenergic receptor. As noted, it is somewhat analogous to the rhodopsin kinase. Such highly specific receptor kinases, which can phosphorylate only the agonist-occupied form of a receptor, represent a potentially elegant mechanism for controlling the function of receptors in a fashion which is linked to their physiological stimulation. How widespread such kinases are, and the actual roles which they play in regulating receptor function, remain to be determined. Finally, it should be stressed that although this review has focused on the regulatory role of receptor phosphorylation, it is by no means our intent to suggest that receptors are the only locus for physiological control of sensitivity to hormone and drug reaction. There is already evidence that guanine nucleotide regulatory proteins can be regulated, and it seems likely that each of the components of the system, including the adenylate cyclase, are likely to be involved in various forms of complex regulation. To date, however, the receptors represent that component of the system whose regulation we understand in the greatest detail.
Publication Types:
Review
PMID: 3024910 [PubMed - indexed for MEDLINE]
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34: J Am Geriatr Soc. 1985 Mar;33(3):184-8.
The impact of aging on adrenergic receptor function: clinical and biochemical aspects.
Heinsimer JA, Lefkowitz RJ.
From this discussion, several conclusions can be drawn. First, with advancing age there is a decrease in cardiovascular responsiveness and, more specifically, there is a decrease in catecholamine-stimulated chronotropic and inotropic responses. This decreased function has its biochemical correlate in the observation that cyclic AMP levels are decreased in response to isoproterenol infusion in cells or tissues derived from aged organisms. Second, although most work on human circulating cells suggests that beta-adrenergic receptor densities are unchanged, measurements of beta-adrenergic receptor concentrations in various cells from various animals (predominantly rats) have yielded conflicting results. Some of this disparity could be due to the observation that local concentrations of norepinephrine, such as those found intramyocardially, may be very different from those in circulating plasma. Indeed, whereas circulating norepinephrine levels tend to rise with age, the intramyocardial norepinephrine levels tend to fall with senescence. Thus, circulating lymphocytes may or may not be an appropriate model to reflect the catecholamine milieu to which other tissues may be exposed. Accordingly, a note of caution must be entered in terms of extrapolating findings regarding the levels of human lymphocyte beta-adrenergic receptors and cyclic AMP activity to those found, for example, in the human heart. Furthermore, it is likely that age-related changes in adrenergic function may be the result of changes in coupling of receptors to the adenylate cyclase system, as suggested by Feldman and co-workers, and/or changes in steps distal to cyclase activation, as suggested by Guarnieri and colleagues.(ABSTRACT TRUNCATED AT 250 WORDS)
Publication Types:
In Vitro
Review
PMID: 2857740 [PubMed - indexed for MEDLINE]
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35: Mol Cell Endocrinol. 1984 Oct;37(3):245-56.
Receptor-specific mechanisms of desensitization of beta-adrenergic receptor function.
Hertel C, Perkins JP.
beta-Adrenergic receptor (beta AR)-specific, agonist-induced desensitization of adenylate cyclase can be shown in most mammalian cells examined to involve at least three reactions. An initial 'uncoupling' reaction leads to a 40-60% loss of catecholamine-stimulated adenylate cyclase activity at a time when no detectable loss of beta AR has occurred. This process precedes by 45-90 sec the appearance of beta AR in cytoplasmic vesicles. Such beta AR exhibit ligand binding properties consistent with their existence on the inside of membrane vesicles; thus, they appear to be formed by a process of agonist-induced beta AR internalization (endocytosis). A third process results in the loss of beta AR, at least in some cases due to receptor degradation. In general, agonist-induced desensitization or down-regulation reactions do not require protein synthesis. Recovery from the desensitized states does not require protein synthesis, whereas recovery from beta AR down-regulation (degraded receptors) requires new receptor synthesis. Agonist-induced beta AR desensitization and down-regulation reactions appear to have much in common with the process of polypeptide hormone-induced receptor down-regulation. The availability of a large number of ligands (agonists, partial agonists and antagonists) for the beta AR should allow the use of this receptor system to gain unique insights into the general processes of ligand-induced, cell surface receptor endocytosis.
Publication Types:
Review
PMID: 6094283 [PubMed - indexed for MEDLINE]
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36: Nippon Rinsho. 1975 Jul 10;33(7):2254-63.
[Contractile function of the heart. Adrenergic beta receptor blockaders and cardiac function]
[Article in Japanese]
Ito M, Kanaya S, Mashiba H.
Publication Types:
Review
PMID: 523 [PubMed - indexed for MEDLINE]
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37: Drugs. 1974;7(1):130-8.
Adverse effects of beta-adrenergic receptor blocking drugs on respiratory function.
Beumer HM.
Publication Types:
Comparative Study
Review
PMID: 4151697 [PubMed - indexed for MEDLINE]
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