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Advances in Adrenergic Receptor Biology

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 39392

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Prof. Dr. Paola Bagnoli

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Department of Biology, University of Pisa, 56127 Pisa, Italy
Interests: animal models; ocular diseases; retinal function; neurodegeneration; neuroprotection; angiogenesis; inflammation; anti-angiogenic and anti-inflammatory compounds; dietary supplementation; eye health
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Dear Colleagues,

We had to wait until the early 1900s to establish that cathecolamines, including epinephrine and norepinephrine, are released by the stimulation of the sympathetic nerves and that their opposite effects on body tissues depend on (at least) two different types of detector mechanisms (later on designated as adrenoceptors). Then, in 1948, adrenoceptors were first divided into two major types, α and β, based on their pharmacological properties, to be subsequently subdivided into the subfamilies of α₁-, α₂-, and β-adrenoceptors, including three subtypes each. Adrenoreceptor subtypes are involved in many biological processes, and their ligands are effective against various diseases, depending on efficacy and tolerability. Historically, much emphasis has been given to β adrenoceptors, since β blockers mainly targeting β₁ and β₂ subtypes were introduced in cardiovascular therapy more than 50 years ago, with well-known pharmacological and safety profiles. In addition, the recently identified β₃ subtypes have been proven to be interesting pharmacological targets for their unique localization and their low rate of desensitization. Most of the adrenoceptors have become targets for the treatment or prevention of many prevalent diseases, and there are several examples of disturbed adrenoceptor function that can be involved in clinical disorders. In this scenario, recent findings suggest that targeting adrenoceptor signaling can be a novel therapeutic approach for treating several diseases. Moreover, recent preclinical evidence indicate that additional pathologies can be counteracted by targeting adrenoceptors. For instance, the use of adrenoceptor ligands in animal models has been demonstrated to be effective in treating the retinopathy of prematurity, nephrogenic diabetes insipidus, diabetes mellitus, rheumatoid arthritis, and other inflammatory diseases. In addition, potential protective properties of mirabegron, a β₃adrenoceptor agonist that was developed and marketed for clinical use in overactive bladder disease, have been recently reported in patients at high risk for developing heart failure. On the other hand, the complex pharmacological profile of adrenoceptor ligands and the still unknown aspects of their regulation have limited their use and applicability in humans. Therefore, in this Special Issue, we invite you to improve the current knowledge of any aspect of the expression, function, and regulation of adrenoceptors and their subtypes with original research articles as well as to summarize the current state of this complex field with compelling reviews. Studies at the cellular level, in isolated organs or in vivo models of pathologies involving adrenoceptors, must be addressed in order to provide novel mechanistic insights into adrenoceptor function. Manuscripts providing translational value will be particularly welcome.

Prof. Paola Bagnoli
Guest Editor

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Keywords

adrenoceptor signaling
adrenoceptor properties and ligands
sympathetic regulation
adrenoceptor-associated diseases
animal models

Published Papers (11 papers)

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Research

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22 pages, 2990 KiB

Open AccessArticle

The Anti-Inflammatory Effect of the β1-Adrenergic Receptor Antagonist Metoprolol on High Glucose Treated Human Microvascular Retinal Endothelial Cells

by Giovanni Giurdanella, Anna Longo, Alfio Distefano, Melania Olivieri, Martina Cristaldi, Alessia Cosentino, Aleksandra Agafonova, Nunzia Caporarello, Gabriella Lupo and Carmelina Daniela Anfuso

Cells 2022, 11(1), 51; https://doi.org/10.3390/cells11010051 - 24 Dec 2021

Cited by 6 | Viewed by 2786

Abstract

Hyperglycemia-induced impairment of the blood-retinal barrier represents the main pathological event in diabetic retinopathy that is elicited by a reduced cellular response to an accumulation of reactive oxygen species (ROS) and increased inflammation. The purpose of the study was to evaluate whether the selective β1-adrenoreceptor (β1-AR) antagonist metoprolol could modulate the inflammatory response to hyperglycemic conditions. For this purpose, human retinal endothelial cells (HREC) were treated with normal (5 mM) or high glucose (25 mM, HG) in the presence of metoprolol (10 μM), epinephrine (1 μM), or both compounds. Metoprolol prevented both the HG-induced reduction of cell viability (MTT assays) and the modulation of the angiogenic potential of HREC (tube formation assays) reducing the TNF-α, IL-1β, and VEGF mRNA levels (qRT-PCR). Moreover, metoprolol prevented the increase in phospho-ERK1/2, phospho-cPLA₂, COX2, and protein levels (Western blot) as well as counteracting the translocation of ERK1/2 and cPLA₂ (high-content screening). Metoprolol reduced ROS accumulation in HG-stimulated HREC by activating the anti-oxidative cellular response mediated by the Keap1/Nrf2/HO-1 pathway. In conclusion, metoprolol exerted a dual effect on HG-stimulated HREC, decreasing the activation of the pro-inflammatory ERK1/2/cPLA₂/COX2 axis, and counteracting ROS accumulation by activating the Keap1/Nrf2/HO-1 pathway. Full article

(This article belongs to the Special Issue Advances in Adrenergic Receptor Biology)

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18 pages, 1741 KiB

Open AccessArticle

Effects of (a Combination of) the Beta₂-Adrenoceptor Agonist Indacaterol and the Muscarinic Receptor Antagonist Glycopyrrolate on Intrapulmonary Airway Constriction

by Harm Maarsingh, Anouk Oldenburger, Bing Han, Annet B. Zuidhof, Carolina R. S. Elzinga, Wim Timens, Herman Meurs, Ramadan B. Sopi and Martina Schmidt

Cells 2021, 10(5), 1237; https://doi.org/10.3390/cells10051237 - 18 May 2021

Cited by 4 | Viewed by 2369

Abstract

Expression of bronchodilatory β₂-adrenoceptors and bronchoconstrictive muscarinic M₃-receptors alter with airway size. In COPD, (a combination of) β₂-agonists and muscarinic M₃-antagonists (anticholinergics) are used as bronchodilators. We studied whether differential receptor expression in large and small airways affects the response to β₂-agonists and anticholinergics in COPD. Bronchoprotection by indacaterol (β₂-agonist) and glycopyrrolate (anticholinergic) against methacholine- and EFS-induced constrictions of large and small airways was measured in guinea pig and human lung slices using video-assisted microscopy. In guinea pig lung slices, glycopyrrolate (1, 3 and 10 nM) concentration-dependently protected against methacholine- and EFS-induced constrictions, with no differences between large and small intrapulmonary airways. Indacaterol (0.01, 0.1, 1 and 10 μM) also provided concentration-dependent protection, which was greater in large airways against methacholine and in small airways against EFS. Indacaterol (10 μM) and glycopyrrolate (10 nM) normalized small airway hyperresponsiveness in COPD lung slices. Synergy of low indacaterol (10 nM) and glycopyrrolate (1 nM) concentrations was greater in LPS-challenged guinea pigs (COPD model) compared to saline-challenged controls. In conclusion, glycopyrrolate similarly protects large and small airways, whereas the protective effect of indacaterol in the small, but not the large, airways depends on the contractile stimulus used. Moreover, findings in a guinea pig model indicate that the synergistic bronchoprotective effect of indacaterol and glycopyrrolate is enhanced in COPD. Full article

(This article belongs to the Special Issue Advances in Adrenergic Receptor Biology)

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16 pages, 12245 KiB

Open AccessArticle

Effect of Beta 3 Adrenoreceptor Modulation on Patency of the Ductus Arteriosus

by Alessandro Pini, Camilla Fazi, Patrizia Nardini, Maura Calvani, Sergio Fabbri, Alessandro Guerrini, Giulia Forni, Giancarlo La Marca, Arianna Carolina Rosa and Luca Filippi

Cells 2020, 9(12), 2625; https://doi.org/10.3390/cells9122625 - 7 Dec 2020

Cited by 7 | Viewed by 2091

Abstract

β3-adrenoreceptor (β3-AR), a G-protein coupled receptor, has peculiar regulatory properties in response to oxygen and widespread localization. β3-AR is expressed in the most frequent neoplasms, also occurring in pregnant women, and its blockade reduces tumor growth, indicating β3-AR-blockers as a promising alternative to antineoplastic drugs during pregnancy. However, β3-AR involvement in prenatal morphogenesis and the consequences of its blockade for the fetus remain unknown. In this study, after the demonstrated expression of β3-AR in endothelial and smooth muscle cells of ductus arteriosus (DA), C57BL/6 pregnant mice were acutely treated at 18.5 of gestational day (GD) with indomethacin or with the selective β3-AR antagonist SR59230A, or chronically exposed to SR59230A from 15.5 to 18.5 GD. Six hours after the last treatment, fetuses were collected. Furthermore, newborn mice were treated straight after birth with BRL37344, a β3-AR agonist, and sacrificed after 7 h. SR59230A, at the doses demonstrated effective in reducing cancer progression (10 and 20 mg/kg) in acute and chronic mode, did not induce fetal DA constriction and did not impair the DA ability to close after birth, whereas at the highest dose (40 mg/kg), it was shown to cause DA constriction and preterm-delivery. BRL37344 administered immediately after birth did not alter the physiological DA closure. Full article

(This article belongs to the Special Issue Advances in Adrenergic Receptor Biology)

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20 pages, 8534 KiB

Open AccessArticle

Novel Insights into Beta 2 Adrenergic Receptor Function in the rd10 Model of Retinitis Pigmentosa

by Maurizio Cammalleri, Massimo Dal Monte, Rosario Amato, Dominga Lapi and Paola Bagnoli

Cells 2020, 9(9), 2060; https://doi.org/10.3390/cells9092060 - 9 Sep 2020

Cited by 3 | Viewed by 2445

Abstract

Background: In retinitis pigmentosa (RP), inherited rod death is followed by cone loss and blindness. Why cones die is still a matter of consideration. Here, we investigate the pathogenic role of the sympathetic transmission in the rd10 mouse model of RP. Methods: Retinal levels of beta adrenergic receptor (BAR) 2 and norepinephrine (NE) were measured. After administration of the BAR1/2 blocker propranolol or the hypoxia-inducible factor (HIF)-1 activator dimethyloxalylglycine (DMOG), retinal levels of HIF-1α, BAR2 or proteins involved in BAR2 desensitization were also measured. In DMOG treated mice, expression and localization of BAR2, inflammatory markers and cone arrestin were determined. Finally, rd10 mice were subjected to electroretinogram (ERG) analysis to assess rod and cone function. Results: In the rd10 retina, BAR2 overexpression and NE accumulation were found, with BAR2 immunoreactivity localized to Müller cells. BAR2 overexpression was likely due to desensitization defects. Upregulated levels of BAR2 were drastically reduced by propranolol that also restored desensitization defects. Due to the low level of HIF-1 consequent to the hyperoxic environment in the rd10 retina, we hypothesized a link between HIF-1 and BAR2. HIF-1α stabilization with DMOG resulted in i. increased HIF-1α accumulation, ii. decreased BAR2 levels, iii. restored desensitization processes, iv. reduced expression of inflammatory markers and v. increased cone survival without improved retinal function. Conclusions: Our results support a pathogenic role of the sympathetic system in RP that might help to understand why rd10 mice show a positive response to BAR blockers. Full article

(This article belongs to the Special Issue Advances in Adrenergic Receptor Biology)

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14 pages, 2153 KiB

Open AccessArticle

Agonist Effects of Propranolol on Non-Tumor Human Breast Cells

by Lucía Gargiulo, Ezequiel Mariano Rivero, Nicolás di Siervi, Edgardo David Buzzi, Mariano Gabriel Buffone, Carlos Alberto Davio, Isabel Alicia Lüthy and Ariana Bruzzone

Cells 2020, 9(4), 1036; https://doi.org/10.3390/cells9041036 - 22 Apr 2020

Cited by 7 | Viewed by 4546

Abstract

The β-blocker propranolol (PROP) has been proposed as a repurposed treatment for breast cancer. The similarity of action between β-agonists and antagonists found on breast cells encouraged us to compare PROP and isoproterenol (ISO, agonist) signaling pathways on a human breast cell line. Cell proliferation was measured by cell counting and DNA-synthesis. Cell adhesion was measured counting the cells that remained adhered to the plastic after different treatments. Changes in actin cytoskeleton were observed by fluorescence staining and Western Blot. ISO and PROP caused a diminution of cell proliferation and an increase of cell adhesion, reverted by the pure β-antagonist ICI-118551. ISO and PROP induced a reorganization of actin cytoskeleton increasing F-actin, p-COFILIN and p-LIMK. While ISO elicited a marked enhancement of cAMP concentrations and an increase of vasodilator-stimulated phosphoprotein (VASP) and cAMP response element-binding protein (CREB) phosphorylation, PROP did not. Clathrin-mediated endocytosis inhibition or β-arrestin1 dominant-negative mutant abrogated PROP-induced cell adhesion and COFILIN phosphorylation. The fact that PROP has been proposed as an adjuvant drug for breast cancer makes it necessary to determine the specific action of PROP in breast models. These results provide an explanation for the discrepancies observed between experimental results and clinical evidence. Full article

(This article belongs to the Special Issue Advances in Adrenergic Receptor Biology)

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Review

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21 pages, 1385 KiB

Open AccessReview

The Role of Adrenoceptors in the Retina

by Yue Ruan, Tobias Böhmer, Subao Jiang and Adrian Gericke

Cells 2020, 9(12), 2594; https://doi.org/10.3390/cells9122594 - 3 Dec 2020

Cited by 8 | Viewed by 4664

Abstract

The retina is a part of the central nervous system, a thin multilayer with neuronal lamination, responsible for detecting, preprocessing, and sending visual information to the brain. Many retinal diseases are characterized by hemodynamic perturbations and neurodegeneration leading to vision loss and reduced quality of life. Since catecholamines and respective bindings sites have been characterized in the retina, we systematically reviewed the literature with regard to retinal expression, distribution and function of alpha₁ (α₁)-, alpha₂ (α₂)-, and beta (β)-adrenoceptors (ARs). Moreover, we discuss the role of the individual adrenoceptors as targets for the treatment of retinal diseases. Full article

(This article belongs to the Special Issue Advances in Adrenergic Receptor Biology)

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22 pages, 2095 KiB

Open AccessReview

The Beta3 Adrenergic Receptor in Healthy and Pathological Cardiovascular Tissues

by Lauriane Y. M. Michel, Charlotte Farah and Jean-Luc Balligand

Cells 2020, 9(12), 2584; https://doi.org/10.3390/cells9122584 - 2 Dec 2020

Cited by 46 | Viewed by 5504

Abstract

The third isotype of beta-adrenoreceptors (β3-AR) has recently come (back) into focus after the observation of its expression in white and beige human adipocytes and its implication in metabolic regulation. This coincides with the recent development and marketing of agonists at the human receptor with superior specificity. Twenty years ago, however, we and others described the expression of β3-AR in human myocardium and its regulation of contractility and cardiac remodeling. Subsequent work from many laboratories has since expanded the characterization of β3-AR involvement in many aspects of cardiovascular physio(patho)logy, justifying the present effort to update current paradigms under the light of the most recent evidence. Full article

(This article belongs to the Special Issue Advances in Adrenergic Receptor Biology)

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30 pages, 452 KiB

Open AccessFeature PaperReview

Expression and Signaling of β-Adrenoceptor Subtypes in the Diabetic Heart

by Betul R. Erdogan, Martin C. Michel and Ebru Arioglu-Inan

Cells 2020, 9(12), 2548; https://doi.org/10.3390/cells9122548 - 26 Nov 2020

Cited by 9 | Viewed by 2512

Abstract

Diabetes is a chronic, endocrine disorder that effects millions of people worldwide. Cardiovascular complications are the major cause of diabetes-related morbidity and mortality. Cardiac β₁- and β₂-adrenoceptor (AR) stimulation mediates positive inotropy and chronotropy, whereas β₃-AR mediates negative inotropic effect. Changes in β-AR responsiveness are thought to be an important factor that contributes to the diabetic cardiac dysfunction. Diabetes related changes in β-AR expression, signaling, and β-AR mediated cardiac function have been studied by several investigators for many years. In the present review, we have screened PubMed database to obtain relevant articles on this topic. Our search has ended up with wide range of different findings about the effect of diabetes on β-AR mediated changes both in molecular and functional level. Considering these inconsistent findings, the effect of diabetes on cardiac β-AR still remains to be clarified. Full article

(This article belongs to the Special Issue Advances in Adrenergic Receptor Biology)

22 pages, 707 KiB

Open AccessReview

Neurohormonal Modulation as a Therapeutic Target in Pulmonary Hypertension

by Inés García-Lunar, Daniel Pereda, Borja Ibanez and Ana García-Álvarez

Cells 2020, 9(11), 2521; https://doi.org/10.3390/cells9112521 - 22 Nov 2020

Cited by 4 | Viewed by 3297

Abstract

The autonomic nervous system (ANS) and renin-angiotensin-aldosterone system (RAAS) are involved in many cardiovascular disorders, including pulmonary hypertension (PH). The current review focuses on the role of the ANS and RAAS activation in PH and updated evidence of potential therapies targeting both systems in this condition, particularly in Groups 1 and 2. State of the art knowledge in preclinical and clinical use of pharmacologic drugs (beta-blockers, beta-three adrenoceptor agonists, or renin-angiotensin-aldosterone signaling drugs) and invasive procedures, such as pulmonary artery denervation, is provided. Full article

(This article belongs to the Special Issue Advances in Adrenergic Receptor Biology)

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23 pages, 1565 KiB

Open AccessReview

Cardiac and Vascular α₁-Adrenoceptors in Congestive Heart Failure: A Systematic Review

by Gizem Kaykı-Mutlu, Olga Papazisi, Meindert Palmen, A. H. Jan Danser, Martin C. Michel and Ebru Arioglu-Inan

Cells 2020, 9(11), 2412; https://doi.org/10.3390/cells9112412 - 4 Nov 2020

Cited by 10 | Viewed by 4153

Abstract

As heart failure (HF) is a devastating health problem worldwide, a better understanding and the development of more effective therapeutic approaches are required. HF is characterized by sympathetic system activation which stimulates α- and β-adrenoceptors (ARs). The exposure of the cardiovascular system to the increased locally released and circulating levels of catecholamines leads to a well-described downregulation and desensitization of β-ARs. However, information on the role of α-AR is limited. We have performed a systematic literature review examining the role of both cardiac and vascular α₁-ARs in HF using 5 databases for our search. All three α₁-AR subtypes (α_1A, α_1B and α_1D) are expressed in human and animal hearts and blood vessels in a tissue-dependent manner. We summarize the changes observed in HF regarding the density, signaling and responses of α₁-ARs. Conflicting findings arise from different studies concerning the influence that HF has on α₁-AR expression and function; in contrast to β-ARs there is no consistent evidence for down-regulation or desensitization of cardiac or vascular α₁-ARs. Whether α₁-ARs are a therapeutic target in HF remains a matter of debate. Full article

(This article belongs to the Special Issue Advances in Adrenergic Receptor Biology)

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28 pages, 1274 KiB

Open AccessReview

A Systematic Review of Inverse Agonism at Adrenoceptor Subtypes

by Martin C. Michel, Martina B. Michel-Reher and Peter Hein

Cells 2020, 9(9), 1923; https://doi.org/10.3390/cells9091923 - 19 Aug 2020

Cited by 14 | Viewed by 3896

Abstract

As many, if not most, ligands at G protein-coupled receptor antagonists are inverse agonists, we systematically reviewed inverse agonism at the nine adrenoceptor subtypes. Except for β₃-adrenoceptors, inverse agonism has been reported for each of the adrenoceptor subtypes, most often for β₂-adrenoceptors, including endogenously expressed receptors in human tissues. As with other receptors, the detection and degree of inverse agonism depend on the cells and tissues under investigation, i.e., they are greatest when the model has a high intrinsic tone/constitutive activity for the response being studied. Accordingly, they may differ between parts of a tissue, for instance, atria vs. ventricles of the heart, and within a cell type, between cellular responses. The basal tone of endogenously expressed receptors is often low, leading to less consistent detection and a lesser extent of observed inverse agonism. Extent inverse agonism depends on specific molecular properties of a compound, but inverse agonism appears to be more common in certain chemical classes. While inverse agonism is a fascinating facet in attempts to mechanistically understand observed drug effects, we are skeptical whether an a priori definition of the extent of inverse agonism in the target product profile of a developmental candidate is a meaningful option in drug discovery and development. Full article

(This article belongs to the Special Issue Advances in Adrenergic Receptor Biology)

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