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Heart Failure Clinics Jul 2019Despite improvements in management and therapeutic approach in the last decades, heart failure is still associated with high mortality rates. The sustained enhancement... (Review)
Review
Despite improvements in management and therapeutic approach in the last decades, heart failure is still associated with high mortality rates. The sustained enhancement in the sympathetic nervous system tone, observed in patients with heart failure, causes alteration in β-adrenergic receptor signaling and function. This latter phenomenon is the result of several heart failure-related molecular abnormalities involving adrenergic receptors, G-protein-coupled receptor kinases, and β-arrestins. This article summarizes novel encouraging preclinical strategies to reactivate β-adrenergic receptor signaling in heart failure, including pharmacologic and gene therapy approaches, and attempts to translate acquired notions into the clinical setting.
Topics: Heart Failure; Humans; Polymorphism, Genetic; Receptors, Adrenergic, beta; Signal Transduction
PubMed: 31079699
DOI: 10.1016/j.hfc.2019.02.009 -
Progress in Molecular Biology and... 2019The β-adrenergic receptor (β-AR) is an important regulator of various physiological functions, such as thermogenesis in brown adipose tissue, lipolysis in white... (Review)
Review
The β-adrenergic receptor (β-AR) is an important regulator of various physiological functions, such as thermogenesis in brown adipose tissue, lipolysis in white adipose tissue, negative inotropic effect in cardiomyocyte, and relaxation in blood vessel. The activation of β-AR by its agonists is shown to have metabolic (antiobesity and antidiabetic) and cardiovascular effects in animal models, highlighting β-AR as a potential therapeutic target in the treatment of several human diseases. Moreover, a substantial number of studies performed on different populations have identified some β-AR polymorphic variants associated with obesity, diabetes, cardiovascular diseases, and other disorders. The clinical phenotypes and functional characteristics of these variants provide insights into potential pathophysiological roles of β-AR in the development of these diseases.
Topics: Animals; Heterozygote; Humans; Polymorphism, Genetic; Receptors, Adrenergic, beta-3; Signal Transduction
PubMed: 30711031
DOI: 10.1016/bs.pmbts.2018.09.003 -
Current Protocols Jan 2023β-adrenergic receptors regulate cardiac function in both the healthy and failing heart. Their expression is decreased in heart failure due to chronic overactivation of...
β-adrenergic receptors regulate cardiac function in both the healthy and failing heart. Their expression is decreased in heart failure due to chronic overactivation of the sympathetic nervous system, contributing to declines in cardiac function and disease progression. Furthermore, therapies that prevent β-adrenergic receptor downregulation or restore β-adrenergic receptor levels are beneficial, making the determination of cardiac β-adrenergic receptor expression in the heart an important consideration. Although quantitative RT-PCR can provide an indication of β-adrenergic receptor density and subtype expression, mRNA levels do not always correlate with functional protein levels. Additionally, antibodies to β-adrenergic receptors lack specificity, making immunoblotting and other antibody-based techniques unreliable. Radioligand binding assays were developed over 50 years ago and remain the gold standard for quantifying β-adrenergic receptor densities in biological samples. This technique capitalizes on the binding of high-affinity, highly specific ligands to receptors and can give quantifiable levels of receptor expression. Furthermore, competition assays using subtype-selective antagonists generate binding profiles and can differentiate β-adrenergic receptor subtype expression in cardiac tissue. This article focuses on the quantification of β-adrenergic receptors in the heart using saturation and competition radioligand binding techniques to quantify β-adrenergic receptor density and ligand affinities in cardiac membranes. © 2023 Wiley Periodicals LLC. Basic Protocol: Radioligand binding to quantify adrenergic receptor expression in the heart.
Topics: Humans; Adrenergic Agents; Receptors, Adrenergic; Heart; Receptors, Adrenergic, beta; Heart Failure
PubMed: 36602296
DOI: 10.1002/cpz1.649 -
Pharmacology & Therapeutics Jan 2004The biological effects of epinephrine and norepinephrine are mediated via 9 different adrenergic receptor subtypes, which all belong to the superfamily of G... (Review)
Review
The biological effects of epinephrine and norepinephrine are mediated via 9 different adrenergic receptor subtypes, which all belong to the superfamily of G protein-coupled receptors. Although pharmacological ligands for adrenergic receptors have an important place in medical therapy, the full therapeutic potential of the 9 adrenergic receptor subtypes has not been explored yet. To dissect the physiological relevance of adrenergic receptor subtype diversity, gene-targeted mouse models carrying deletions in these receptor genes ("knockout mice") have been generated. This review gives an overview of the phenotypes observed in mice deficient in adrenergic receptors and discusses the therapeutic relevance of subtype-specific drug therapy.
Topics: Animals; Mice; Mice, Knockout; Models, Animal; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Signal Transduction
PubMed: 14729393
DOI: 10.1016/j.pharmthera.2003.10.004 -
Annual Review of Pharmacology and... 1994Investigators have not yet reached a consensus on the number and signaling mechanisms of alpha 1-adrenergic receptor (AR) subtypes. Two native subtypes (alpha 1A and... (Review)
Review
Investigators have not yet reached a consensus on the number and signaling mechanisms of alpha 1-adrenergic receptor (AR) subtypes. Two native subtypes (alpha 1A and alpha 1B) can be distinguished pharmacologically, and three subtypes (alpha 1B, alpha 1C, and alpha 1D) have been cloned. One of the cloned subtypes (alpha 1D) was originally thought to encode the pharmacologically defined alpha 1A subtype. However, recent data suggest otherwise, and many investigators now agree that the alpha 1A subtype has probably not yet been cloned. The relationship between the cloned receptors and the native subtypes must be understood, and any additional cDNA clones obtained, before the drug specificities and second messenger pathways of alpha 1-AR subtypes can be clearly defined. Little is yet known about the cellular and tissue distribution of these subtypes, their developmental profiles, or their functional importance. Molecular cloning of complementary DNA sequences for the remaining subtypes will help to clarify the number and properties of these subtypes. Identification of drugs that can selectively target particular subtypes is an important goal that may result in therapeutic advances in numerous disease states, including benign prostatic hyperplasia. The newly recognized complexity of the adrenergic receptors presents us with both important challenges and new therapeutic targets. The potential impact of this field on medical therapeutics remains to be clearly defined.
Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Cloning, Molecular; Humans; Receptors, Adrenergic, alpha-1; Signal Transduction
PubMed: 8042847
DOI: 10.1146/annurev.pa.34.040194.001001 -
Annual Review of Physiology 1991Multiple mechanisms contribute to the regulation of G protein-coupled receptors and their transmembrane signaling. Post-translational modifications of the receptors,... (Review)
Review
Multiple mechanisms contribute to the regulation of G protein-coupled receptors and their transmembrane signaling. Post-translational modifications of the receptors, such as phosphorylation, and changes in receptor gene expression can occur in either a strictly agonist-dependent fashion or through second messenger-mediated autoregulation. We have shown that modulation of receptor gene expression contributes to the responsiveness of adrenergic and related receptors. Recent evidence for post-transcriptional regulation, as well as the stimulation of transcription in an autoregulatory manner, indicates the unanticipated variety and complexity of mechanisms regulating adrenergic receptor responsiveness.
Topics: Animals; Gene Expression Regulation; Humans; Receptors, Adrenergic; Up-Regulation
PubMed: 2042970
DOI: 10.1146/annurev.ph.53.030191.002433 -
Journal of Cardiovascular Pharmacology Sep 2022Adrenergic receptors are critical regulators of cardiac function with profound effects on cardiac output during sympathetic stimulation. Chronic stimulation of the...
Adrenergic receptors are critical regulators of cardiac function with profound effects on cardiac output during sympathetic stimulation. Chronic stimulation of the adrenergic system of the heart under conditions of cardiac stress leads to cardiac dysfunction, hypertrophy, and ultimately failure. Emerging data have revealed that G protein-coupled receptors in intracellular compartments are functionally active and regulate distinct cellular processes from those at the cell surface. β2 adrenergic receptors internalize onto endosomes in various cell types where they have recently been shown to continue to stimulate cAMP production to selectively regulate gene expression. Other studies have identified β1 adrenergic receptors at the nuclear envelope and the Golgi apparatus. Here, we discuss data on signaling by β1 and β2 adrenergic receptors in the heart and the possible influence of their subcellular locations on their divergent physiological functions in cardiac myocytes and in cardiac pathology. Understanding the relative roles of these receptors at these locations could have a significant impact on pharmacological targeting of these receptors for the treatment of heart failure and cardiac diseases.
Topics: Heart Failure; Humans; Myocytes, Cardiac; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-2; Signal Transduction
PubMed: 35881897
DOI: 10.1097/FJC.0000000000001324 -
Brazilian Journal of Biology = Revista... 2022The pineal melatonin (N-acetyl-5-methoxytryptamine) is a molecule associated in a way or another with probably all physiological systems, aiming to fulfil its functional...
The pineal melatonin (N-acetyl-5-methoxytryptamine) is a molecule associated in a way or another with probably all physiological systems, aiming to fulfil its functional integrative roles in central nervous system activity, sleep and wakefulness cycles, energy metabolism and thermoregulation, immune, reproductive, endocrine, cardiovascular, respiratory and excretory systems. Within this context, the present study aimed to assess in silico the formation of complexes between ligand melatonin and other potential receptor proteins by molecular docking analyses. The main steps established in this experimental procedure were: a) search and selection of the 3D structure of the melatonin from DrugBank; b) search and selection of 3D structures of other target receptor proteins using STRING, protein BLAST and database PDB; and c) formation of the complexes between melatonin and receptors selected using AutoDock4.0 server by molecular docking analyses. High reliability score and significant similarity were only identified between type 1B melatonin and alpha-2A adrenergic receptor. Thus, molecular docking assays were carried out using ligand melatonin and crystallographic structures of the alpha-2A adrenergic receptor coupled to an antagonist (ID PDB 6kux) and a partial agonist (ID PDB 6kuy) available in the database PDB. Binding energy values of -6.79 and -6.98 kcal/mol and structural stability by non-covalent intermolecular interactions were predicted during the formation of complexes between melatonin and alpha-2A adrenergic receptor 6kux and 6kuy, respectively. In this way, the findings described in current study may indicate strong interactions between melatonin and adrenoceptors, suggesting its possible partial agonist effect on the activation of the alfa-2A adrenergic receptor.
Topics: Ligands; Melatonin; Molecular Docking Simulation; Receptors, Adrenergic, alpha; Receptors, Adrenergic, alpha-2; Reproducibility of Results
PubMed: 35920463
DOI: 10.1590/1519-6984.261624 -
Heart Failure Reviews Mar 2000In the failing heart, several changes occur in cardiac adrenergic receptor-signal transduction pathways. The most striking of these changes occur in beta-ARs, and of the... (Comparative Study)
Comparative Study Review
In the failing heart, several changes occur in cardiac adrenergic receptor-signal transduction pathways. The most striking of these changes occur in beta-ARs, and of the changes in beta-adrenergic receptors, beta1-receptor down-regulation is the most prominent. Other changes include uncoupling of beta2-adrenergic receptors and increased activity of the inhibitory G-protein, Gi. Most of these changes appear to be related to increased activity of the adrenergic nervous system, i.e. increased exposure to norepinephrine. Antagonists of the adrenergic nervous system improve left ventricular function and outcome in patients with heart failure. This fact supports the notion that activation of these neurohormonal systems exerts a net long-term detrimental effect on the natural history of chronic heart failure and that myocardial adrenergic desensitization phenomena are at least partially adaptive in the setting of left ventricular dysfunction.
Topics: Animals; Down-Regulation; Female; Heart Failure; Humans; Male; Mice; Norepinephrine; Receptors, Adrenergic; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Sensitivity and Specificity; Signal Transduction
PubMed: 16228912
DOI: 10.1023/A:1009885822076 -
Advances in Experimental Medicine and... 2023Catecholamine stimulation over adrenergic receptors results in a state of hypercoagulability. Chronic stress involves the release and increase in circulation of...
Catecholamine stimulation over adrenergic receptors results in a state of hypercoagulability. Chronic stress involves the release and increase in circulation of catecholamines and other stress related hormones. Numerous observational studies in human have related stressful scenarios to several coagulation variables, but controlled stimulation with agonists or antagonists to adrenergic receptors are scarce. This systematic review is aimed at presenting an updated appraisal of the effect of adrenergic receptor modulation on variables related to human hemostasis by systematically reviewing the effect of adrenergic receptor-targeting drugs on scale variables related to hemostasis. By searching 3 databases for articles published between January 1st 2011 and February 16th, 2022 reporting effects on coagulation parameters from stimulation with α- or β-adrenergic receptor targeting drugs in humans regardless of baseline condition, excluding records different from original research and those not addressing the main aim of this systematic review. Risk of bias assessed using the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2). Tables describing a pro-thrombotic anti-fibrinolytic state induced after β-adrenergic receptor agonist stimulation and the opposite after α-, β-adrenergic receptor antagonist stimulation were synthesized from 4 eligible records by comparing hemostasis-related variables to their baseline. Notwithstanding this low number of records, experimental interventions included were sound and mostly unbiased, results were coherent, and outcomes were biologically plausible. In summary, this systematic review provides a critical systematic assessment and an updated elaboration, and its shortcomings highlight the need for further investigation in the field of hematology.
Topics: Catecholamines; Receptors, Adrenergic; Adrenergic Agents; Hemostasis; Humans; Stress, Physiological; Blood Coagulation
PubMed: 37093421
DOI: 10.1007/978-3-031-26163-3_3