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Glia Sep 2022Norepinephrine exerts powerful influences on the metabolic, neuroprotective and immunoregulatory functions of astrocytes. Until recently, all effects of norepinephrine...
Norepinephrine exerts powerful influences on the metabolic, neuroprotective and immunoregulatory functions of astrocytes. Until recently, all effects of norepinephrine were believed to be mediated by receptors localized exclusively to the plasma membrane. However, recent studies in cardiomyocytes have identified adrenergic receptors localized to intracellular membranes, including Golgi and inner nuclear membranes, and have shown that norepinephrine can access these receptors via transporter-mediated uptake. We recently identified a high-capacity norepinephrine transporter, organic cation transporter 3 (OCT3), densely localized to outer nuclear membranes in astrocytes, suggesting that adrenergic signaling may also occur at the inner nuclear membrane in these cells. Here, we used immunofluorescence and western blot to show that β -adrenergic receptors are localized to astrocyte inner nuclear membranes; that key adrenergic signaling partners are present in astrocyte nuclei; and that OCT3 and other catecholamine transporters are localized to astrocyte plasma and nuclear membranes. To test the functionality of nuclear membrane β -adrenergic receptors, we monitored real-time protein kinase A (PKA) activity in astrocyte nuclei using a fluorescent biosensor. Treatment of astrocytes with norepinephrine induced rapid increases in PKA activity in the nuclear compartment. Pretreatment of astrocytes with inhibitors of catecholamine uptake blocked rapid norepinephrine-induced increases in nuclear PKA activity. These studies, the first to document functional adrenergic receptors at the nuclear membrane in any central nervous system cell, reveal a novel mechanism by which norepinephrine may directly influence nuclear processes. This mechanism may contribute to previously described neuroprotective, metabolic and immunoregulatory actions of norepinephrine.
Topics: Adrenergic Agents; Astrocytes; Catecholamines; Norepinephrine; Nuclear Envelope; Receptors, Adrenergic; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-1
PubMed: 35589612
DOI: 10.1002/glia.24219 -
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 -
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 -
Sheng Li Xue Bao : [Acta Physiologica... Apr 2020Gliomas are malignant tumors with strong invasiveness. The current treatment strategy is surgical treatment assisted by a variety of radiotherapies, chemotherapies and... (Review)
Review
Gliomas are malignant tumors with strong invasiveness. The current treatment strategy is surgical treatment assisted by a variety of radiotherapies, chemotherapies and immunotherapies. However, the curative efficacy is limited. Adrenergic receptor (AR) is an important stress hormone receptor, which is highly involved in the regulation of the tumorigenesis and progression of various tumors by activating different downstream signal transduction pathways. Recent studies have shown that AR is dysregulated in glioma cells and tissues, and plays an important role in a series of biological behaviors such as tumorigenesis, invasion and metastasis of glioma. This article reviews the research progress of AR in the field of glioma in recent years, which provides a theoretical basis for the prevention and treatment of glioma targeting the AR.
Topics: Brain Neoplasms; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Glioma; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Receptors, Adrenergic; Signal Transduction
PubMed: 32328617
DOI: No ID Found -
American Journal of Physiology.... Feb 2001The atypical beta3-adrenergic receptor (AR) agonist CGP-12177 has been used to define a novel atypical beta-AR subtype, the putative beta4-AR. Recent evaluation of... (Review)
Review
The atypical beta3-adrenergic receptor (AR) agonist CGP-12177 has been used to define a novel atypical beta-AR subtype, the putative beta4-AR. Recent evaluation of recombinant beta-AR subtypes and beta-AR-deficient mice, however, has established the identity of the pharmacological beta4-AR as a novel state of the beta1-AR protein. The ability of aryloxypropanolamine ligands like CGP-12177 to independently interact with agonist and antagonist states of the beta1-AR has important implications regarding receptor classification and the potential development of tissue-specific beta-AR agonists.
Topics: Animals; Humans; Protein Isoforms; Receptors, Adrenergic, beta; Technology, Pharmaceutical
PubMed: 11158920
DOI: 10.1152/ajpendo.2001.280.2.E199 -
BioMed Research International 2020Adrenaline quickly inhibits the release of histamine from mast cells. Besides -adrenergic receptors, several in vitro studies also indicate the involvement of...
BACKGROUND
Adrenaline quickly inhibits the release of histamine from mast cells. Besides -adrenergic receptors, several in vitro studies also indicate the involvement of -adrenergic receptors in the process of exocytosis. Since exocytosis in mast cells can be detected electrophysiologically by the changes in the membrane capacitance (Cm), its continuous monitoring in the presence of drugs would determine their mast cell-stabilizing properties.
METHODS
Employing the whole-cell patch-clamp technique in rat peritoneal mast cells, we examined the effects of adrenaline on the degranulation of mast cells and the increase in the Cm during exocytosis. We also examined the degranulation of mast cells in the presence or absence of -adrenergic receptor agonists or antagonists.
RESULTS
Adrenaline dose-dependently suppressed the GTP--S-induced increase in the Cm and inhibited the degranulation from mast cells, which was almost completely erased in the presence of butoxamine, a -adrenergic receptor antagonist. Among -adrenergic receptor agonists or antagonists, high-dose prazosin, a selective -adrenergic receptor antagonist, significantly reduced the ratio of degranulating mast cells and suppressed the increase in the Cm. Additionally, prazosin augmented the inhibitory effects of adrenaline on the degranulation of mast cells.
CONCLUSIONS
This study provided electrophysiological evidence for the first time that adrenaline dose-dependently inhibited the process of exocytosis, confirming its usefulness as a potent mast cell stabilizer. The pharmacological blockade of -adrenergic receptor by prazosin synergistically potentiated such mast cell-stabilizing property of adrenaline, which is primarily mediated by -adrenergic receptors.
Topics: Animals; Electrophysiology; Epinephrine; Exocytosis; Humans; Male; Mast Cells; Prazosin; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-1
PubMed: 32461978
DOI: 10.1155/2020/3214186 -
Biochimica Et Biophysica Acta.... Sep 2017Even though there are hundreds of reports in the published literature supporting the hypothesis that G protein-coupled receptors (GPCR) form and function as dimers this...
Even though there are hundreds of reports in the published literature supporting the hypothesis that G protein-coupled receptors (GPCR) form and function as dimers this remains a highly controversial area of research and mechanisms governing homodimer formation are poorly understood. Crystal structures revealing homodimers have been reported for many different GPCR. For adrenergic receptors, a potential dimer interface involving transmembrane domain 1 (TMD1) and helix 8 (H8) was identified in crystal structures of the beta-adrenergic (β-AR) and β-AR. The purpose of this study was to investigate a potential role for TMD1 and H8 in dimerization and plasma membrane expression of functional β-AR. Charged residues at the base of TMD1 and in the distal portion of H8 were replaced, singly and in combination, with non-polar residues or residues of opposite charge. Wild type and mutant β-AR, tagged with YFP and expressed in HEK293 cells, were evaluated for plasma membrane expression and function. Homodimer formation was evaluated using bioluminescence resonance energy transfer, bimolecular fluorescence complementation, and fluorescence correlation spectroscopy. Amino acid substitutions at the base of TMD1 and in the distal portion of H8 disrupted homodimer formation and caused receptors to be retained in the endoplasmic reticulum. Mutations in the proximal region of H8 did not disrupt dimerization but did interfere with plasma membrane expression. This study provides biophysical evidence linking a potential TMD1/H8 interface with ER export and the expression of functional β-AR on the plasma membrane. This article is part of a Special Issue entitled: Interactions between membrane receptors in cellular membranes edited by Kalina Hristova.
Topics: Cell Membrane; Crystallography, X-Ray; Endoplasmic Reticulum; Gene Expression Regulation; HEK293 Cells; Humans; Mutation; Protein Conformation; Protein Domains; Protein Multimerization; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-2; Signal Transduction; Spectrometry, Fluorescence
PubMed: 27993566
DOI: 10.1016/j.bbamem.2016.12.007 -
Molecular Cell Aug 2021The β-adrenergic receptor (βAR) is predominantly expressed in adipose tissue and urinary bladder and has emerged as an attractive drug target for the treatment of type...
The β-adrenergic receptor (βAR) is predominantly expressed in adipose tissue and urinary bladder and has emerged as an attractive drug target for the treatment of type 2 diabetes, obesity, and overactive bladder (OAB). Here, we report the cryogenic electron microscopy structure of the βAR-G signaling complex with the selective agonist mirabegron, a first-in-class drug for OAB. Comparison of this structure with the previously reported βAR and βAR structures reveals a receptor activation mechanism upon mirabegron binding to the orthosteric site. Notably, the narrower exosite in βAR creates a perpendicular pocket for mirabegron. Mutational analyses suggest that a combination of both the exosite shape and the amino-acid-residue substitutions defines the drug selectivity of the βAR agonists. Our findings provide a molecular basis for βAR subtype selectivity, allowing the design of more-selective agents with fewer adverse effects.
Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Animals; Binding Sites; Cryoelectron Microscopy; Dogs; Humans; Models, Molecular; Molecular Dynamics Simulation; Receptors, Adrenergic, beta-3; Thiazoles
PubMed: 34314699
DOI: 10.1016/j.molcel.2021.06.024 -
Neuroscience and Biobehavioral Reviews Nov 2012Dysfunction in noradrenergic neurotransmission has long been theorized to occur in depressive disorders. The α2 adrenergic receptor (AR) family, as a group of key... (Review)
Review
Dysfunction in noradrenergic neurotransmission has long been theorized to occur in depressive disorders. The α2 adrenergic receptor (AR) family, as a group of key players in regulating the noradrenergic system, has been investigated for involvement in the neurobiology of depression and mechanisms of antidepressant therapies. However, a clear picture of the α2ARs in depressive disorders has not been established due to the existence of apparently conflicting findings in the literature. In this article, we report that a careful accounting of methodological differences within the literature can resolve the present lack of consensus on involvement of α2ARs in depression. In particular, the pharmacological properties of the radioligand (e.g. agonist versus antagonist) utilized for determining receptor density are crucial in determining study outcome. Upregulation of α2AR density detected by radiolabeled agonists but not by antagonists in patients with depressive disorders suggests a selective increase in the density of high-affinity conformational state α2ARs, which is indicative of enhanced G protein coupling to the receptor. Importantly, this high-affinity state α2AR upregulation can be normalized with antidepressant treatments. Thus, depressive disorders appear to be associated with increased α2AR sensitivity and responsiveness, which may represent a physiological basis for the putative noradrenergic dysfunction in depressive disorders. In addition, we review changes in some key α2AR accessory proteins in depressive disorders and discuss their potential contribution to α2AR dysfunction.
Topics: Animals; Antidepressive Agents; Depressive Disorder; Gene Expression Regulation; Humans; Models, Biological; Neurobiology; Receptors, Adrenergic, alpha-2
PubMed: 22910678
DOI: 10.1016/j.neubiorev.2012.07.011 -
Cancer Biomarkers : Section a of... 2013The importance of adrenergic pathways in cancer has long been suspected, but now there is mounting epidemiological, preclinical, and clinical evidence of its importance... (Review)
Review
The importance of adrenergic pathways in cancer has long been suspected, but now there is mounting epidemiological, preclinical, and clinical evidence of its importance in gynecologic cancers. To date, most of these effects are mediated primarily through the beta 2 adrenergic receptor activation of the tumor cell cyclic AMP-protein kinase A signaling pathway. This review will discuss the current knowledge about the neuroendocrine stress response in gynecologic tumor biology.
Topics: Animals; Female; Genital Neoplasms, Female; Humans; Receptors, Adrenergic; Signal Transduction
PubMed: 23912486
DOI: 10.3233/CBM-130324