Emerging concepts and therapeutic implications of β-adrenergic receptor subtype signaling

doi:10.1016/j.pharmthera.2005.04.006

Pharmacology & Therapeutics

Volume 108, Issue 3, December 2005, Pages 257-268

https://doi.org/10.1016/j.pharmthera.2005.04.006 Get rights and content

Abstract

The stimulation of β-adrenergic receptor (βAR) plays a pivotal role in regulating myocardial function and morphology in the normal and failing heart. Three genetically and pharmacologically distinct βAR subtypes, β₁AR, β₂AR, and β₃AR, are identified in various types of cells. While both β₁AR and β₂AR, the predominant βAR subtypes expressed in the heart of many mammalian species including human, are coupled to the G_s–adenylyl cyclase–cAMP–PKA pathway, β₂AR dually activates pertussis toxin-sensitive G_i proteins. During acute stimulation, β₂AR–G_i coupling partially inhibits the G_s-mediated positive contractile and relaxant effects via a G_i–G_βγ–phosphoinositide 3-kinase (PI3K)-dependent mechanism in adult rodent cardiomyocytes. More importantly, persistent β₁AR stimulation evokes a multitude of cardiac toxic effects, including myocyte apoptosis and hypertrophy, via a calmodulin-dependent protein kinase II (CaMKII)-, rather than cAMP–PKA-, dependent mechanism in rodent heart in vivo and cultured cardiomyocytes. In contrast, persistent β₂AR activation protects myocardium by a cell survival pathway involving G_i, PI3K, and Akt. In this review, we attempt to highlight the distinct functionalities and signaling mechanisms of these βAR subtypes and discuss how these subtype-specific properties of βARs might affect the pathogenesis of congestive heart failure (CHF) and the therapeutic effectiveness of certain β-blockers in the treatment of congestive heart failure.

Introduction

β-adrenergic receptor (βAR) stimulation by the sympathetic nervous system or circulating catecholamines regulates a wide range of biological processes, from heart pacemaker activity, myocardial contractility, and relaxation to vascular and bronchia smooth muscle tone, to glucose and lipid metabolism. βARs belong to G protein-coupled receptors (GPCRs) characterized by a conserved structural topology of 7-transmembrane domains (7TM) with an extracellular N-terminus and an intracellular C-terminus. In 1967, Lands et al. (1967) classified βARs into β₁AR and β₂AR as cardiac/lipolytic and vascular/bronchial subtypes, respectively, based on the rank order of potency of a series of structurally related catecholamines, including epinephrine and norepinephrine in different tissues. Over the past 4 decades, the accumulation of a wealth of knowledge of βAR subtype entities and their signaling mechanisms has rendered the βAR as a model system of the GPCR superfamily. Beginning in the early 1980s, Lefkowitz and colleagues developed a series of techniques to purify and reconstitute adrenergic receptors. In 1986, they successfully cloned the gene and cDNA encoding the hamster β₂AR (Dixon et al., 1986). This important breakthrough paved the road for the field of GPCR biology. In the next several years, many GPCRs were cloned, including human β₁AR (Frielle et al., 1987) and human β₃AR (Emorine et al., 1989). The human β₁AR and β₂AR share 54% homology in their amino acid sequences, while β₃AR shares 51% and 46% homology with β₁AR and β₂AR amino acid sequences, respectively.

Although cardiac βAR was initially thought to be β₁AR, radioligand binding or pharmacological assays revealed the existence of cardiac β₂AR and β₃AR. There is now compelling evidence indicating that the predominant βAR subtypes expressed in the heart are β₁AR and β₂AR in many mammalian species, including human (Brodde, 1988, Brodde, 1991). These βAR subtypes fulfill different, even opposite, physiological and pathophysiological roles via activating subtype-specific signaling pathways in the heart. These characteristics of cardiac βAR subtypes bear important etiological and therapeutic implications for congestive heart failure (CHF).

Section snippets

Distinct signaling properties of cardiac β₁AR and β₂AR revealed from pharmacological and genetic approaches

Cardiac βAR signaling and functional properties were traditionally studied using pharmacological assays with selective agonists and antagonists. In particular, using highly selective β₁AR and β₂AR antagonists, CGP 20712A (Dooley et al., 1986, Baker, 2005) and ICI 118,551 (O'Donnell & Wanstall, 1980, Baker, 2005), respectively, in conjunction with radioligand binding with [¹²⁵I]-Cyanopindolol, the densities of these βAR subtypes have been characterized in normal and failing hearts of human and

Possible causal relation between β-adrenergic receptor subtype signaling and the pathogenesis of heart failure

A possible causal relation between βAR stimulation and the pathogenesis of CHF have evolved progressively during the past 3 decades. Because a hallmark of CHF is the diminished cardiac contractile performance, the early prevalent view was that the reduced βAR contractile support is a causal factor for the progression of heart failure (Braunwald & Bristow, 2000). However, clinical administration of βAR agonists unexpectedly increased the mortality of patients with CHF, despite the short-term

Concluding remarks

Recent progress in cardiac βAR signaling is marked by discoveries on subtype-specific and time-dependent signaling mechanisms, receptor heterodimerization, dual G protein coupling, and several new intracellular signaling pathways. These advances have greatly deepened our understanding of the causal relation between βAR stimulation and the pathogenesis of CHF. The distinct β₁AR and β₂AR biology and signaling properties also shed new light on the clinical variation in the effectiveness of

Acknowledgments

The authors would like to thank Dr. H. Cheng for critical comments and discussions. This work is supported by the Chinese National Natural Science Foundation (30100215), Peking University 985 Project, Chinese National Key Project 973 (G2000056906), and Chinese Young Investigator Award (30225036), and, in part, by NIH intramural research grant (WZW and RPX).

References (120)

J.D. Bisognano et al.
Myocardial-directed overexpression of the human β₁-adrenergic receptor in transgenic mice
J Mol Cell Cardiol
(2000)
M. Bohm et al.
Radioimmunochemical quantification of Gi_α in right and left ventricles from patients with ischaemic and dilated cardiomyopathy and predominant left ventricular failure
J Mol Cell Cardiol
(1994)
O.E. Brodde
The functional importance of β₁ and β₂ adrenoceptors in the human heart
Am J Cardiol
(1988)
A.J. Chruscinski et al.
Targeted disruption of the β₂-adrenergic receptor gene
J Biol Chem
(1999)
C. Communal et al.
p38 mitogen-activated protein kinase pathway protects adult rat ventricular myocytes against β-adrenergic receptor-stimulated apoptosis. Evidence for G_i-dependent activation
J Biol Chem
(2000)
D.J. Dooley et al.
CGP 20712 A: a useful tool for quantitating β₁- and β₂-adrenoceptors
Eur J Pharmacol
(1986)
K.E. Fladmark et al.
Ca²⁺/calmodulin-dependent protein kinase II is required for microcystin-induced apoptosis
J Biol Chem
(2002)
S.A. Green et al.
A polymorphism of the human β₂-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor
J Biol Chem
(1993)
T.E. Hebert et al.
A peptide derived from a beta2-adrenergic receptor transmembrane domain inhibits both receptor dimerization and activation
J Biol Chem
(1996)
A.R. Kompa et al.
Desensitization of cardiac β-adrenoceptor signaling with heart failure produced by myocardial infarction in the rat. Evidence for the role of G_i but not G_s or phosphorylating proteins
J Mol Cell Cardiol
(1999)

M. Kuschel et al.

Gi protein-mediated functional compartmentalization of cardiac β₂-adrenergic signaling

J Biol Chem

(1999)

C. Lavoie et al.

β₁/β₂-Adrenergic receptor heterodimerization regulates β₂-adrenergic receptor internalization and ERK signaling efficacy

J Biol Chem

(2002)

D.A. Mason et al.

A gain-of-function polymorphism in a G-protein coupling domain of the human β₁-adrenergic receptor

J Biol Chem

(1999)

J.F. Mercier et al.

Quantitative assessment of β₁- and β₂-adrenergic receptor homo- and heterodimerization by bioluminescence resonance energy transfer

J Biol Chem

(2002)

M. Metra et al.

Effects of short- and long-term carvedilol administration on rest and exercise hemodynamic variables, exercise capacity and clinical conditions in patients with idiopathic dilated cardiomyopathy

J Am Coll Cardiol

(1994)

C. Morisco et al.

The Akt-glycogen synthase kinase 3β pathway regulates transcription of atrial natriuretic factor induced by β-adrenergic receptor stimulation in cardiac myocytes

J Biol Chem

(2000)

S.R. O'Donnell et al.

Evidence that ICI 118, 551 is a potent, highly β₂-selective adrenoceptor antagonist and can be used to characterize β-adrenoceptor populations in tissues

Life Sci

(1980)

S.L. Olsen et al.

Carvedilol improves left ventricular function and symptoms in chronic heart failure: a double-blind randomized study

J Am Coll Cardiol

(1995)

P.A. Poole-Wilson et al.

Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial

Lancet

(2003)

D.K. Rohrer et al.

Cardiovascular and metabolic alterations in mice lacking both β₁- and β₂-adrenergic receptors

J Biol Chem

(1999)

M. Sato et al.

Loss of β-adrenoceptor response in myocytes overexpressing the Na⁺/Ca²⁺-exchanger

J Mol Cell Cardiol

(2004)

Y. Shizukuda et al.

Subtype specific roles of β-adrenergic receptors in apoptosis of adult rat ventricular myocytes

J Mol Cell Cardiol

(2002)

I. Ahmet et al.

Beneficial effects of chronic pharmacological manipulation of β-adrenoreceptor subtype signaling in rodent dilated ischemic cardiomyopathy

Circulation

(2004)

R.A. Altschuld et al.

Response of failing canine and human heart cells to β2-adrenergic stimulation

Circulation

(1995)

K.M. Anderson et al.

The myocardial beta-adrenergic system in spontaneously hypertensive heart failure (SHHF) rats

Hypertension

(1999)

C.L. Antos et al.

Dilated cardiomyopathy and sudden death resulting from constitutive activation of protein kinase A

Circ Res

(2001)

J.G. Baker

The selectivity of β-adrenoceptor antagonists at the human β₁, β₂ and β₃ adrenoceptors

Br J Pharmacol

(2005)

M.A. Bogoyevitch et al.

Stimulation of the stress-activated mitogen-activated protein kinase subfamilies in perfused heart. p38/RK mitogen-activated protein kinases and c-Jun N-terminal kinases are activated by ischemia/reperfusion

Circ Res

(1996)

E. Braunwald et al.

Congestive heart failure: fifty years of progress

Circulation

(2000)

M.R. Bristow

Mechanistic and clinical rationales for using β-blockers in heart failure

J Card Fail

(2000)

M.R. Bristow et al.

β₁- and β₂-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective β₁-receptor down-regulation in heart failure

Circ Res

(1986)

M.R. Bristow et al.

Selective versus nonselective β-blockade for heart failure therapy: are there lessons to be learned from the COMET trial?

J Card Fail

(2004)

O.E. Brodde

β₁- and β₂-adrenoceptors in the human heart: properties, function, and alterations in chronic heart failure

Pharmacol Rev

(1991)

L.A. Brown et al.

The effect of pertussis toxin on β-adrenoceptor responses in isolated cardiac myocytes from noradrenaline-treated guinea-pigs and patients with cardiac failure

Br J Pharmacol

(1992)

A. Chesley et al.

The β₂-adrenergic receptor delivers an antiapoptotic signal to cardiac myocytes through Gi-dependent coupling to phosphatidylinositol 3′-kinase

Circ Res

(2000)

M.C. Cho et al.

Enhanced contractility and decreased β-adrenergic receptor kinase-1 in mice lacking endogenous norepinephrine and epinephrine

Circulation

(1999)

J.N. Cohn et al.

Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure

N Engl J Med

(1984)

C. Communal et al.

Opposing effects of β₁- and β₂-adrenergic receptors on cardiac myocyte apoptosis: role of a pertussis toxin-sensitive G protein

Circulation

(1999)

Y. Daaka et al.

Switching of the coupling of the β₂-adrenergic receptor to different G proteins by protein kinase A

Nature

(1997)

R.A. Dixon et al.

Cloning of the gene and cDNA for mammalian β-adrenergic receptor and homology with rhodopsin

Nature

(1986)

G.W. Dorn et al.

Low- and high-level transgenic expression of β₂-adrenergic receptors differentially affect cardiac hypertrophy and function in Gα_q-overexpressing mice

Proc Natl Acad Sci U S A

(1999)

L.J. Emorine et al.

Molecular characterization of the human β₃-adrenergic receptor

Science

(1989)

S. Engelhardt et al.

Progressive hypertrophy and heart failure in β₁-adrenergic receptor transgenic mice

Proc Natl Acad Sci U S A

(1999)

T. Eschenhagen et al.

Increased messenger RNA level of the inhibitory G protein alpha subunit Gi_α-2 in human end-stage heart failure

Circ Res

(1992)

K. Freeman et al.

Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy

J Clin Invest

(2001)

T. Frielle et al.

Cloning of the cDNA for the human β₁-adrenergic receptor

Proc Natl Acad Sci U S A

(1987)

M.H. Gao et al.

Adenylyl cyclase increases responsiveness to catecholamine stimulation in transgenic mice

Circulation

(1999)

C. Gauthier et al.

Functional β₃-adrenoceptor in the human heart

J Clin Invest

(1996)

C. Gauthier et al.

The negative inotropic effect of β₃-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle

J Clin Invest

(1998)

H. Gong et al.

Specific β₂AR blocker ICI 118,551 actively decreases contraction through a Gi-coupled form of the β₂AR in myocytes from failing human heart

Circulation

(2002)

Cited by (83)

Targeting β3-adrenergic receptor signaling inhibits neuroblastoma cell growth via suppressing the mTOR pathway
2019, Biochemical and Biophysical Research Communications
Citation Excerpt :
β-ARs comprise three subtypes, namely, β1-AR, β2-AR and β3-AR. Among these receptors, β1-AR and β2-AR are predominantly expressed in the heart of many mammalian species [16], whereas β3-AR is mainly expressed in adipose tissues and plays a pivotal role in lipolysis, the thermogenesis of adipose tissue and the mediation of glucose metabolism [17,18]. Recent studies have revealed that the β-AR pathways are closely related to the tumorigenesis and aggressive progression of tumors, with β2-AR being the most widely studied in this regard.
Neuroblastoma (NB), the most common extracranial solid tumor in childhood, always leads to an unfavorable prognosis. β3-adrenergic receptor (β3-AR) signaling plays an important role in lipid metabolism. Although previous studies have focused mainly on the role of β2-AR in tumor cells; there are few studies about the cancer-related function of β3-AR. Herein, we showed that β3-AR expression was significantly increased in clinical NB tissue compared with that in the less malignant ganglioneuroma (GN) and ganglioneuroblastoma (GNB) tissues. Further cellular assays demonstrated that treatment of NB cells with SR59230A (a specific β3-AR antagonist) suppressed NB cells growth and colony formation, and siRNA knockdown of β3-AR expression also inhibited NB cell proliferation. The mechanistic study revealed that β3-AR knockdown and SR59230A inhibited the phosphorylation and thereby the activation of the mTOR/p70S6K pathway. Activation of the mTOR pathway with the activator MHY1485 reversed the inhibitory effect of SR59230A on NB cell growth. Above all, our study clarifies a novel regulatory role of β3-AR in NB cell growth and provides a potent therapeutic strategy for this disease by specific targeting of the β3-AR pathway.
PM<inf>2.5</inf>-induced ADRB2 hypermethylation contributed to cardiac dysfunction through cardiomyocytes apoptosis via PI3K/Akt pathway
2019, Environment International
Long-term exposure to fine particulate matter (PM_2.5) can causally contribute to progression of atherosclerosis, risk of ischemic heart disease and death, but the underlying mechanism is little known. Since DNA methylation impacts the process of heart disease, it might be useful in exploring potential mechanistic pathways linking PM_2.5 exposure and heart disease.
Here, we investigated the PM_2.5-induced ADRB2 hypermethylation and the involving epigenetic mechanism of PM_2.5-induced cardiomyocytes apoptosis and cardiac dysfunction.
In vitro, PM_2.5 markedly augmented cardiotoxicity including oxidative damage and apoptosis in cardiomyocytes AC16 as well as epigenetic alteration. DNA methylation profiling revealed a significant gene-ADRB2 was involved in the cardiac relative GO and KEGG pathways. Methylation chip and Bisulfite Sequencing PCR (BSP) both identified the hypermethylation status of ADRB2 which encodes β2-Adrenergic receptor (β2AR). Mechanistic study showed ADRB2 hypermethylation-induced down-regulation of β2AR inhibited PI3K/Akt and then activated Bcl-2/BAX and p53 pathway in AC16. The transgenic cell lines showed over-expression of ADRB2 weakened the PM_2.5-induced cardiomyocytes apoptosis in opposite way, but was augmented by PI3K inhibitor (LY294002). In vivo, echocardiography showed the heart contractile function was decreased after SD rats intratracheal instillation of PM_2.5 for 30 days. The myocardial interstitial edema, myocardial gap expansion and myofibril disorder in PM_2.5 treated group were observed in rats heart tissue. What's more, basal expression of β2AR and VEGFR2 decreased in heart tissue as the dosage of PM_2.5 increasing, meanwhile PM_2.5 markedly attenuated PI3K/Akt pathway followed by augmented Bcl-2/BAX and p53 pathway, thus caused a greater number of TUNEL positive cardiomyocytes resulted in cardiac dysfunction in vivo.
PM_2.5 exposure could cause the myocardial ADRB2 hypermethylation and activate the β2AR/PI3K/Akt pathway, resulted in PM_2.5-induced cardiomyocytes apoptosis and cardiac dysfunction. Our study suggested that the ADRB2 demethylation or ADRB2/β2AR activation may serve as a potential pathway to prevent cardiac dysfunction induced by PM_2.5 exposure.
Calmodulin inhibition of human RyR2 channels requires phosphorylation of RyR2-S2808 or RyR2-S2814
2019, Journal of Molecular and Cellular Cardiology
Citation Excerpt :
Ex vivo reduction in phosphorylation of S2808 in sheep by the phosphatase PP1 abolished CaM inhibition, reproducing the healthy human phenotype. Several studies have shown that the β2-adrenergic receptor pathway activated by adrenaline, particularly during stress, is predominantly through a stimulatory Gs,α-protein-cyclic AMP-PKA pathway in human heart [44,45] as opposed to dual Gs,α-inhibitory Gi -protein pathways in other animals, [46–48] which may explain differences in RyR2 phosphorylation and hence the difference in regulation by CaM between humans and other animals. In heart failure, altered RyR2 S-oxidation S-nitrosylation and phosphorylation increase the SR Ca2+ leak through RyR2. [42,43]
Calmodulin (CaM) is a Ca-binding protein that binds to, and can directly inhibit cardiac ryanodine receptor calcium release channels (RyR2). Animal studies have shown that RyR2 hyperphosphorylation reduces CaM binding to RyR2 in failing hearts, but data are lacking on how CaM regulates human RyR2 and how this regulation is affected by RyR2 phosphorylation. Physiological concentrations of CaM (100 nM) inhibited the diastolic activity of RyR2 isolated from failing human hearts by ~50% but had no effect on RyR2 from healthy human hearts. Using FRET between donor-FKBP12.6 and acceptor-CaM bound to RyR2, we determined that CaM binds to RyR2 from healthy human heart with a K_d = 121 ± 14 nM. Ex-vivo phosphorylation/dephosphorylation experiments suggested that the divergent CaM regulation of healthy and failing human RyR2 was caused by differences in RyR2 phosphorylation by protein kinase A and Ca-CaM-dependent kinase II. Ca²⁺-spark measurements in murine cardiomyocytes harbouring RyR2 phosphomimetic or phosphoablated mutants at S2814 and S2808 suggest that phosphorylation of residues corresponding to either human RyR2-S2808 or S2814 is both necessary and sufficient for RyR2 regulation by CaM. Our results challenge the current concept that CaM universally functions as a canonical inhibitor of RyR2 across species. Rather, CaM's biological action on human RyR2 appears to be more nuanced, with inhibitory activity only on phosphorylated RyR2 channels, which occurs during exercise or in patients with heart failure.
Cardiac Adenylyl Cyclase and Phosphodiesterase Expression Profiles Vary by Age, Disease, and Chronic Phosphodiesterase Inhibitor Treatment
2017, Journal of Cardiac Failure
Citation Excerpt :
AC6 is known to complex with A-kinase anchoring protein 5 and caveolin-3 to mediate β-adrenergic stimulation of calcium transients in adult murine cardiac myocytes,19 and disruption of AC6 promotes development of myocyte apoptosis and HF in response to chronic catecholamine or pressure-overload stress.20–22 It has been suggested that β2-adrenergic receptors may preferentially couple with AC6 at surface sarcolemma to activate cell survival pathways through activation of phosphatidylinositol 3-kinase/Akt signaling in the heart.17,23–26 Therefore, the increase in AC6 may be a compensatory and possibly protective mechanism in adult DCM induced by chronic PDE3i treatment, or it could reflect a clinical bias toward PDE3i treatment being initiated in patients with more severe HF (despite DCM subjects treated or not treated with PDE3i having equivalent ejection fractions and all DCM subjects having end-stage HF).
Pediatric heart failure (HF) patients have a suboptimal response to traditional HF medications, although phosphodiesterase-3 inhibition (PDE3i) has been used with greater success than in the adult HF population. We hypothesized that molecular alterations specific to children with HF and HF etiology may affect response to treatment.
Adenylyl cyclase (AC) and phosphodiesterase (PDE) isoforms were quantified by means of quantitative real-time polymerase chain reaction in explanted myocardium from adults with dilated cardiomyopathy (DCM), children with DCM, and children with single-ventricle congenital heart disease of right ventricular morphology (SRV). AC and PDE expression profiles were uniquely regulated in each subject group and demonstratde distinct changes in response to chronic PDE3i. There was unique up-regulation of AC5 in adult DCM with PDE3i (fold change 2.415; P = .043), AC2 in pediatric DCM (fold change 2.396; P = .0067), and PDE1C in pediatric SRV (fold change 1.836; P = .032). Remarkably, PDE5A expression was consistently increased across all age and disease groups.
Unique regulation of AC and PDE isoforms supports a differential molecular adaptation to HF in children compared with adults, and may help identify mechanisms specific to the pathogenesis of pediatric HF. Greater understanding of these differences will help optimize medical therapies based on age and disease process.
New signal transduction paradigms in anthracycline-induced cardiotoxicity
2016, Biochimica et Biophysica Acta - Molecular Cell Research
Citation Excerpt :
However, the role of βARs in anthracycline-dependent cardiotoxicity is still poorly characterized. Recent studies uncover a potential involvement of these receptors in mediating the iatrogenic effects of doxorubicin and in particular highlight a cardiotoxic role of β1ARs, while β2ARs appear to be cardioprotective [89]. Evidence indicates that activation of β2ARs but not β1ARs reduces doxorubicin-induced apoptosis in H9c2 cells.
Anthracyclines, such as doxorubicin, are the most potent and widely used chemotherapeutic agents for the treatment of a variety of human cancers, including solid tumors and hematological malignancies. However, their clinical use is hampered by severe cardiotoxic side effects and cancer therapy-related heart disease has become a leading cause of morbidity and mortality among cancer survivors. The identification of therapeutic strategies limiting anthracycline cardiotoxicity with preserved antitumor efficacy thus represents the current challenge of cardio-oncologists. Anthracycline cardiotoxicity has been originally ascribed to the ability of this class of drugs to disrupt iron metabolism and generate excess of reactive oxygen species (ROS). However, small clinical trials with iron chelators and anti-oxidants failed to provide any benefit and suggested that doxorubicin cardiotoxicity is not solely due to redox cycling. New emerging explanations include anthracycline-dependent regulation of major signaling pathways controlling DNA damage response, cardiomyocyte survival, cardiac inflammation, energetic stress and gene expression modulation. This review will summarize recent studies unraveling the complex web of mechanisms of doxorubicin-mediated cardiotoxicity, and identifying new druggable players for the prevention of heart disease in cancer patients. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.
Coupling of β<inf>1</inf>-adrenergic receptor to type 5 adenylyl cyclase and its physiological relevance in cardiac myocytes
2015, Biochemical and Biophysical Research Communications
Citation Excerpt :
Since AC5 is known to play an important role in cardiac apoptosis [8,11,21], these data support the idea that β1-AR is coupled preferentially to AC5. In order to examine the mechanism underlying the opposing effects of β1-AR and β2-AR on cardiac myocytes [2], we adopted two approaches. Firstly, we examined the effects of dd-Ado, a specific AC5 inhibitor [21] on cAMP accumulation and cardiac apoptosis induced by ISO under conditions of selective β1-AR or β2-AR stimulation.
Myocardial β-adrenergic receptor (β-AR) β₁- and β₂-subtypes are highly homologous, but play opposite roles in cardiac apoptosis and heart failure, as do cardiac adenylyl cyclase (AC) subtypes 5 (AC5) and 6 (AC6): β₁-AR and AC5 promote cardiac remodeling, while β₂-AR and AC6 activate cell survival pathways. However, the mechanisms involved remain poorly understood. We hypothesized that AC5 is coupled preferentially to β₁-AR rather than β₂-AR, and we examined this idea by means of pharmacological and genetic approaches. We found that selective inhibition of AC5 with 2′5′-dideoxyadenosine significantly suppressed cAMP accumulation and cardiac apoptosis induced by selective β₁-AR stimulation, but had no effect on cAMP accumulation and cardiac apoptosis in response to selective β₂-AR stimulation. The results of selective stimulation of β₁-AR and β₂-AR in neonatal cardiac myocytes prepared from wild-type and AC5-knockout mice were also consistent with the idea that β₁-AR selectively couples with AC5. We believe these results are helpful for understanding the mechanisms underlying the different roles of AR subtypes in healthy and diseased hearts.

View all citing articles on Scopus

View full text

Associate editor: P. MolenaarEmerging concepts and therapeutic implications of β-adrenergic receptor subtype signaling

Abstract

Introduction

Section snippets

Distinct signaling properties of cardiac β1AR and β2AR revealed from pharmacological and genetic approaches

Possible causal relation between β-adrenergic receptor subtype signaling and the pathogenesis of heart failure

Concluding remarks

Acknowledgments

J Mol Cell Cardiol

J Mol Cell Cardiol

Am J Cardiol

J Biol Chem

J Biol Chem

Eur J Pharmacol

J Biol Chem

J Biol Chem

J Biol Chem

J Mol Cell Cardiol

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Am Coll Cardiol

J Biol Chem

Life Sci

J Am Coll Cardiol

Lancet

J Biol Chem

J Mol Cell Cardiol

J Mol Cell Cardiol

Beneficial effects of chronic pharmacological manipulation of β-adrenoreceptor subtype signaling in rodent dilated ischemic cardiomyopathy

Circulation

Response of failing canine and human heart cells to β2-adrenergic stimulation

Circulation

The myocardial beta-adrenergic system in spontaneously hypertensive heart failure (SHHF) rats

Hypertension

Dilated cardiomyopathy and sudden death resulting from constitutive activation of protein kinase A

Circ Res

The selectivity of β-adrenoceptor antagonists at the human β1, β2 and β3 adrenoceptors

Br J Pharmacol

Stimulation of the stress-activated mitogen-activated protein kinase subfamilies in perfused heart. p38/RK mitogen-activated protein kinases and c-Jun N-terminal kinases are activated by ischemia/reperfusion

Circ Res

Congestive heart failure: fifty years of progress

Circulation

Mechanistic and clinical rationales for using β-blockers in heart failure

J Card Fail

β1- and β2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective β1-receptor down-regulation in heart failure

Circ Res

Selective versus nonselective β-blockade for heart failure therapy: are there lessons to be learned from the COMET trial?

J Card Fail

β1- and β2-adrenoceptors in the human heart: properties, function, and alterations in chronic heart failure

Pharmacol Rev

The effect of pertussis toxin on β-adrenoceptor responses in isolated cardiac myocytes from noradrenaline-treated guinea-pigs and patients with cardiac failure

Br J Pharmacol

The β2-adrenergic receptor delivers an antiapoptotic signal to cardiac myocytes through Gi-dependent coupling to phosphatidylinositol 3′-kinase

Circ Res

Enhanced contractility and decreased β-adrenergic receptor kinase-1 in mice lacking endogenous norepinephrine and epinephrine

Circulation

Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure

N Engl J Med

Opposing effects of β1- and β2-adrenergic receptors on cardiac myocyte apoptosis: role of a pertussis toxin-sensitive G protein

Circulation

Switching of the coupling of the β2-adrenergic receptor to different G proteins by protein kinase A

Nature

Cloning of the gene and cDNA for mammalian β-adrenergic receptor and homology with rhodopsin

Nature

Low- and high-level transgenic expression of β2-adrenergic receptors differentially affect cardiac hypertrophy and function in Gαq-overexpressing mice

Proc Natl Acad Sci U S A

Molecular characterization of the human β3-adrenergic receptor

Science

Progressive hypertrophy and heart failure in β1-adrenergic receptor transgenic mice

Proc Natl Acad Sci U S A

Increased messenger RNA level of the inhibitory G protein alpha subunit Giα-2 in human end-stage heart failure

Circ Res

Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy

J Clin Invest

Cloning of the cDNA for the human β1-adrenergic receptor

Proc Natl Acad Sci U S A

Adenylyl cyclase increases responsiveness to catecholamine stimulation in transgenic mice

Circulation

Associate editor: P. Molenaar
Emerging concepts and therapeutic implications of β-adrenergic receptor subtype signaling

Distinct signaling properties of cardiac β₁AR and β₂AR revealed from pharmacological and genetic approaches

The selectivity of β-adrenoceptor antagonists at the human β₁, β₂ and β₃ adrenoceptors

β₁- and β₂-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective β₁-receptor down-regulation in heart failure

β₁- and β₂-adrenoceptors in the human heart: properties, function, and alterations in chronic heart failure

The β₂-adrenergic receptor delivers an antiapoptotic signal to cardiac myocytes through Gi-dependent coupling to phosphatidylinositol 3′-kinase

Opposing effects of β₁- and β₂-adrenergic receptors on cardiac myocyte apoptosis: role of a pertussis toxin-sensitive G protein

Switching of the coupling of the β₂-adrenergic receptor to different G proteins by protein kinase A

Low- and high-level transgenic expression of β₂-adrenergic receptors differentially affect cardiac hypertrophy and function in Gα_q-overexpressing mice

Molecular characterization of the human β₃-adrenergic receptor

Progressive hypertrophy and heart failure in β₁-adrenergic receptor transgenic mice

Increased messenger RNA level of the inhibitory G protein alpha subunit Gi_α-2 in human end-stage heart failure

Cloning of the cDNA for the human β₁-adrenergic receptor

Functional β₃-adrenoceptor in the human heart

The negative inotropic effect of β₃-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle

Specific β₂AR blocker ICI 118,551 actively decreases contraction through a Gi-coupled form of the β₂AR in myocytes from failing human heart