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Cells Apr 2019The beta-3 adrenergic receptor (β-AR) is by far the least studied isotype of the beta-adrenergic sub-family. Despite its study being long hampered by the lack of... (Review)
Review
The beta-3 adrenergic receptor (β-AR) is by far the least studied isotype of the beta-adrenergic sub-family. Despite its study being long hampered by the lack of suitable animal and cellular models and inter-species differences, a substantial body of literature on the subject has built up in the last three decades and the physiology of β-AR is unraveling quickly. As will become evident in this work, β-AR is emerging as an appealing target for novel pharmacological approaches in several clinical areas involving metabolic, cardiovascular, urinary, and ocular disease. In this review, we will discuss the most recent advances regarding β-AR signaling and function and summarize how these findings translate, or may do so, into current clinical practice highlighting β-AR's great potential as a novel therapeutic target in a wide range of human conditions.
Topics: Adrenergic beta-3 Receptor Agonists; Adrenergic beta-3 Receptor Antagonists; Animals; Epinephrine; Humans; Norepinephrine; Receptors, Adrenergic, beta-3; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 30995798
DOI: 10.3390/cells8040357 -
International Journal of Molecular... Oct 2021Cardiovascular diseases (CDs) are a major concern in the human race and one of the leading causes of death worldwide. β-Adrenergic receptors (β1-AR and β2-AR) play a...
Cardiovascular diseases (CDs) are a major concern in the human race and one of the leading causes of death worldwide. β-Adrenergic receptors (β1-AR and β2-AR) play a crucial role in the overall regulation of cardiac function. In the present study, structure-based virtual screening, machine learning (ML), and a ligand-based similarity search were conducted for the PubChem database against both β1- and β2-AR. Initially, all docked molecules were screened using the threshold binding energy value. Molecules with a better binding affinity were further used for segregation as active and inactive through ML. The pharmacokinetic assessment was carried out on molecules retained in the above step. Further, similarity searching of the ChEMBL and DrugBank databases was performed. From detailed analysis of the above data, four compounds for each of β1- and β2-AR were found to be promising in nature. A number of critical ligand-binding amino acids formed potential hydrogen bonds and hydrophobic interactions. Finally, a molecular dynamics (MD) simulation study of each molecule bound with the respective target was performed. A number of parameters obtained from the MD simulation trajectories were calculated and substantiated the stability between the protein-ligand complex. Hence, it can be postulated that the final molecules might be crucial for CDs subjected to experimental validation.
Topics: Drug Discovery; Humans; Ligands; Machine Learning; Molecular Dynamics Simulation; Protein Binding; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-2
PubMed: 34681845
DOI: 10.3390/ijms222011191 -
Cellular Signalling Mar 2012Conventional models of G-protein coupled receptor (GPCR) signaling describe cell surface receptors binding to external ligands, such as hormones or circulating peptides,...
Conventional models of G-protein coupled receptor (GPCR) signaling describe cell surface receptors binding to external ligands, such as hormones or circulating peptides, to induce intracellular signaling and a physiologic response. However, recent studies identify new paradigms indicating that GPCRs localize to and signal at the nucleus and that GPCR oligomers can influence receptor function. Previously, we reported that endogenous α1-adrenergic receptors (α1-ARs) localize to and signal at the nuclei in adult cardiac myocytes. In this study, we examined the mechanisms behind α1-AR nuclear localization and how nuclear localization impacted receptor function. We verified that endogenous α1-ARs localized to the nuclear membrane of intact nuclei isolated from wild-type adult cardiac myocytes. Next, we identified and disrupted putative nuclear localization sequences in both the α1A- and α1B-adrenergic receptors, which led to mis-localization of α1-ARs in cultured adult cardiac myocytes. Using these mutants, we demonstrated that nuclear localization was required for α1-signaling in adult cardiac myocytes. We also found that the nuclear export inhibitor leptomycin B inhibited α1-AR signaling, indicating α1-AR signaling must arise in the nucleus in adult cardiac myocytes. Finally, we found that co-localization of the α1-subtypes at the nuclei in adult cardiac myocytes facilitated the formation of receptor oligomers that could affect receptor signaling. In summary, our data indicate that α1-AR nuclear localization can drive the formation of receptor oligomers and regulate signaling in adult cardiac myocytes.
Topics: Animals; Cell Nucleus; Cells, Cultured; Fluorescence Resonance Energy Transfer; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Myocytes, Cardiac; Protein Multimerization; Receptors, Adrenergic, alpha-1; Signal Transduction
PubMed: 22120526
DOI: 10.1016/j.cellsig.2011.11.014 -
Frontiers in Immunology 2023Anti-CD40 agonistic antibody (αCD40), an activator of dendritic cells (DC) can enhance antigen presentation and activate cytotoxic T-cells against poorly immunogenic...
INRODUCTION
Anti-CD40 agonistic antibody (αCD40), an activator of dendritic cells (DC) can enhance antigen presentation and activate cytotoxic T-cells against poorly immunogenic tumors. However, cancer immunotherapy trials also suggest that αCD40 is only moderately effective in patients, falling short of achieving clinical success. Identifying factors that decrease αCD40 immune-stimulating effects can aid the translation of this agent to clinical reality.
METHOD/RESULTS
Here, we reveal that β-adrenergic signaling on DCs directly interferes with αCD40 efficacy in immunologically cold head and neck tumor model. We discovered that β-2 adrenergic receptor (β2AR) activation rewires CD40 signaling in DCs by directly inhibiting the phosphorylation of IκBα and indirectly by upregulating levels of phosphorylated-cAMP response element-binding protein (pCREB). Importantly, the addition of propranolol, a pan β-Blocker reprograms the CD40 pathways, inducing superior tumor regressions, increased infiltration of cytotoxic T-cells, and a reduced burden of regulatory T-cells in tumors compared to monotherapy.
DISCUSSION/CONCLUSION
Thus, our study highlights an important mechanistic link between stress-induced β2AR signaling and reduced αCD40 efficacy in cold tumors, providing a new combinatorial approach to improve clinical outcomes in patients.
Topics: Humans; Dendritic Cells; CD40 Antigens; T-Lymphocytes, Cytotoxic; Neoplasms; Receptors, Adrenergic
PubMed: 37006295
DOI: 10.3389/fimmu.2023.1141712 -
Hearing Research Jan 2012The spiral modiolar artery supplies blood and essential nutrients to the cochlea. Our previous functional study indicates the α(1A)-adrenergic receptor subtype mediates... (Comparative Study)
Comparative Study
The spiral modiolar artery supplies blood and essential nutrients to the cochlea. Our previous functional study indicates the α(1A)-adrenergic receptor subtype mediates vasoconstriction of the gerbil spiral modiolar artery. Although the gerbil cochlea is often used as a model in hearing research, the molecular and pharmacological characteristics of the cloned gerbil α(1a)-adrenergic receptor have not been determined. Thus we cloned, expressed and characterized the gerbil α(1a)-adrenergic receptor and then compared its molecular and pharmacological properties to those of other mammalian α(1a)-adrenergic receptors. The cDNA clone contained 1404 nucleotides, which encoded a 467 amino acid peptide with a deduced sequence having 96.8, 96.4 and 91.6% identity to rat, mouse and human α(1a)-receptors, respectively. We transiently transfected the α(1a)-adrenergic receptor into COS-1 cells and determined its pharmacological characteristics by [(3)H]prazosin binding. Unlabeled prazosin had a K(i) of 0.89±0.1nM. The α(1A)-adrenergic receptor-selective antagonists, 5-methylurapidil and WB-4101, bound with high affinity and had K(i) values of 4.9±1 and 1.0±0.1nM, respectively. BMY-7378, an α(1D)-adrenergic receptor-selective antagonist, bound with low affinity (260±60nM). The 91.6% amino acid sequence identity and K(i)s of the cloned gerbil α(1a)-adrenergic receptor are similar to those of the human α(1a)-adrenergic receptor clone. These results show that the gerbil α(1a)-adrenergic receptor is representative of the human α(1a)-adrenergic receptor, lending validity to the use of the gerbil spiral modiolar artery as a model in studies of vascular disorders of the cochlea.
Topics: Adrenergic alpha-1 Receptor Antagonists; Amino Acid Sequence; Animals; Arteries; COS Cells; Chlorocebus aethiops; Clonidine; Cloning, Molecular; Cochlea; Conserved Sequence; Dioxanes; Dose-Response Relationship, Drug; Gerbillinae; Humans; Mice; Molecular Sequence Data; Piperazines; Prazosin; Radioligand Assay; Rats; Receptors, Adrenergic, alpha-1; Sequence Analysis, Protein; Transfection; Vasoconstriction
PubMed: 22101021
DOI: 10.1016/j.heares.2011.11.002 -
Pacing and Clinical Electrophysiology :... Jun 2016Sympathetic activation in heart failure patients favors the development of ventricular arrhythmias, thus leading to an increased risk of sudden cardiac death. β1 - and...
BACKGROUND
Sympathetic activation in heart failure patients favors the development of ventricular arrhythmias, thus leading to an increased risk of sudden cardiac death. β1 - and β2 -adrenergic receptor polymorphisms have been linked to the risk of sudden death. Implantable cardioverter-defibrillators (ICD) are implanted in a large percentage of heart failure patients, and beyond preventing sudden cardiac death they provide a continuous monitoring of major ventricular arrhythmias and of their own interventions. We investigated whether functionally relevant β1 - and β2 -adrenergic receptor polymorphisms are associated with risk of ICD shocks, as evidenced in ICD memory.
METHODS
311 patients with systolic heart failure were enrolled, and number and timing of shocks in ICD memory were recorded. Four selected polymorphisms were determined: β1 -adrenergic receptor polymorphisms Ser(49) Gly and Arg(389) Gly and β2 -adrenergic receptor polymorphisms Arg(16) Gly and Gln(27) Glu.
RESULTS
Only Ser(49) Gly was significantly correlated with time free from ICD shocks, both considering time to the first event in a Cox model (hazard ratio 2.117), and modeling repeated events with the Andersen-Gill method (hazard ratio 2.088). Gly allele carriers had a higher probability of ICD shock. The relationship remained significant even after adjusting for ejection fraction and beta-blocker dosage (hazard ratio 1.910).
CONCLUSIONS
Data from our study suggest that the β adrenoreceptor Gly 49 allele of the β1 -adrenergic receptor Ser(49) Gly polymorphisms may increase the risk of ICD shock in patients with heart failure, independent of beta-blocker dosage.
Topics: Defibrillators, Implantable; Female; Heart Failure; Humans; Male; Middle Aged; Polymorphism, Genetic; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-2; Risk Factors
PubMed: 27027728
DOI: 10.1111/pace.12860 -
Medicina (Kaunas, Lithuania) 2004Beta-adrenergic receptors have been subdivided into three types: beta1-, beta2- and beta3-adrenergic receptors. beta1-adrenergic receptors are predominant in the heart,... (Comparative Study)
Comparative Study Review
Beta-adrenergic receptors have been subdivided into three types: beta1-, beta2- and beta3-adrenergic receptors. beta1-adrenergic receptors are predominant in the heart, beta2-adrenergic receptors--in the respiratory system, and beta3-adrenergic receptors--in the adipose tissues. However, since 1989, when beta3-adrenergic receptor was cloned, numerous biochemical and functional studies have confirmed its presence in various species and tissues, including the heart. Unlike beta1- and beta2-adrenergic receptors, it has been shown that beta3-adrenergic receptors possess the cardiodepressant effects in human ventricles, what did not fit to its stimulatory properties of adenylyl cyclase in other tissues. In this regard, the role of beta3-adrenergic receptors in the regulation of cardiac function may be of great importance in pathological conditions and remains undetermined, so far. In this review brief characterization of beta3-adrenergic receptors, concerning their structure, function and possible pathophysiological role is provided.
Topics: Adenylyl Cyclases; Adrenergic beta-2 Receptor Antagonists; Adrenergic beta-3 Receptor Antagonists; Adrenergic beta-Agonists; Animals; Atrial Function; CHO Cells; Cardiovascular Physiological Phenomena; Cattle; Cricetinae; Cricetulus; Enzyme Activation; Haplorhini; Heart; Heart Atria; Heart Failure; Heart Ventricles; Humans; Ligands; Mice; Mice, Knockout; Myocardial Contraction; Myocardium; RNA, Messenger; Rats; Receptors, Adrenergic, beta-2; Receptors, Adrenergic, beta-3; Ventricular Function
PubMed: 15170407
DOI: No ID Found -
ELife Oct 2017Beige/brite adipocytes are induced within white adipose tissues (WAT) and, when activated, consume glucose and fatty acids to produce heat. Classically, two stimuli have...
Beige/brite adipocytes are induced within white adipose tissues (WAT) and, when activated, consume glucose and fatty acids to produce heat. Classically, two stimuli have been used to trigger a beiging response: cold temperatures and β3-adrenergic receptor () agonists. These two beiging triggers have been used interchangeably but whether these two stimuli may induce beiging differently at cellular and molecular levels remains unclear. Here, we found that cold-induced beige adipocyte formation requires 1, not , activation. 1 activation stimulates WAT resident perivascular (+) cells to form cold-induced beige adipocytes. In contrast, activation stimulates mature white adipocytes to convert into beige adipocytes. Necessity tests, using mature adipocyte-specific deletion strategies, demonstrated that adipocytes are required and are predominant source to generate -induced, but not cold-induced, beige adipocytes. Collectively, we identify that cold temperatures and agonists activate distinct cellular populations that express different β-adrenergic receptors to induce beige adipogenesis.
Topics: Adipocytes, Beige; Animals; Cell Differentiation; Cold Temperature; Mice, Inbred C57BL; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-3
PubMed: 29019320
DOI: 10.7554/eLife.30329 -
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 -
Sheng Li Xue Bao : [Acta Physiologica... Feb 2004In the heart, stimulation of beta-adrenergic receptors (betaAR) serves as the most powerful means to increase cardiac contractility and relaxation in response to stress... (Review)
Review
In the heart, stimulation of beta-adrenergic receptors (betaAR) serves as the most powerful means to increase cardiac contractility and relaxation in response to stress or a "fight-or-flight" situation. However, sustained beta-adrenergic stimulation promotes pathological cardiac remodeling such as myocyte hypertrophy, apoptosis and necrosis, thus contributing to the pathogenesis of chronic heart failure. Over the past decade, compelling evidence has demonstrated that coexisting cardiac betaAR subtypes, mainly beta(1)AR and beta (2)AR, activate markedly different signaling cascades. As a result, acute beta(1)AR stimulation activates the G(s) -adenylyl cyclase-cAMP-PKA signaling that can broadcast throughout the cell, whereas beta(2)AR-evoked cAMP signaling is spatially and functionally compartmentalized, due to concurrent G(i) activation. Chronic stimulation of beta(1)AR and beta(2)AR elicits opposing effects on the fate of cardiomyocytes: beta(1)AR induces hypertrophy and apoptosis; but beta(2)AR promotes cell survival. The cardiac protective effect of beta(2)AR is mediated by a signaling pathway sequentially involving G(i), G(betagamma), PI3K and Akt. Unexpectedly, beta(1)AR-induced myocyte hypertrophy and apoptosis are independent of the classic cAMP/PKA pathway, but require activation of Ca(2+)/calmodulin-dependent kinase II (CaMK II). The outcomes of cardiac-specific transgenic overexpression of either beta AR subtype in mice have reinforced the fundamentally different functional roles of these betaAR subtypes in governing cardiac remodeling and performance. These new insights regarding betaAR subtype stimulation not only provide clues as to cellular and molecular mechanisms underlying the beneficial effects of beta AR blockers in patients with chronic heart failure, but also delineate rationale for combining selective beta(1)AR blockade with moderate beta(2)AR activation as a potential novel therapy for the treatment of chronic heart failure.
Topics: Adenylyl Cyclases; Animals; Cyclic AMP-Dependent Protein Kinases; GTP-Binding Proteins; Heart; Heart Failure; Humans; Myocardium; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-2; Signal Transduction
PubMed: 14985822
DOI: No ID Found