Subtype-specific β-adrenoceptor signaling pathways in the heart and their potential clinical implications

doi:10.1016/j.tips.2004.05.007

Trends in Pharmacological Sciences

Volume 25, Issue 7, July 2004, Pages 358-365

https://doi.org/10.1016/j.tips.2004.05.007 Get rights and content

Abstract

β-Adrenoceptor stimulation serves as the most powerful means to increase cardiac output in response to stress or exercise. However, sustained β-adrenoceptor stimulation promotes pathological cardiac remodeling such as myocyte hypertrophy and apoptosis, thus contributing to heart failure. Coexisting cardiac β-adrenoceptor subtypes, mainly β₁-adrenoceptors and β₂-adrenoceptors, activate different signaling cascades with β₁-adrenoceptors coupling to G_s and β₂-adrenoceptors coupling to G_s and G_i pathways. As a result, sustained β₂-adrenoceptor stimulation protects cardiomyocytes against apoptosis via a G_i–phosphatidylinositol 3-kinase–protein kinase B pathway, whereas chronic β₁-adrenoceptor stimulation induces myocyte hypertrophy and apoptosis by protein kinase A-independent activation of calmodulin kinase II signaling. These advances in our understanding of β-adrenoceptor subtype signaling identify the mechanisms that underlie the beneficial effects of β-adrenoceptor antagonists and delineate the rationale for combining β₁-adrenoceptor blockade with β₂-adrenoceptor activation as a potential therapy for heart failure.

Section snippets

β₂-Adrenoceptor–G_i signaling compartmentalizes β₂-adrenoceptor–G_s-mediated cAMP signaling

In the heart, β₁-adrenoceptor-activated cAMP signaling increases the phosphorylation of sarcolemmal L-type Ca²⁺ channels and a multitude of intracellular regulatory proteins, including sarcoplasmic reticulum (SR) protein phospholamban (PLB) and myofilaments (troponin I and C protein) [3]. However, β₂-adrenoceptor-mediated cAMP signaling specifically modulates the Ca²⁺ channel without affecting the aforementioned intracellular targets in cardiomyocytes from many mammalian species, including rat

Opposing roles of β-adrenoceptor subtypes in regulating the fate of cardiomyocytes

Apoptosis has been implicated in cardiac ischemic and reperfusion injury and is involved in the transition from cardiac hypertrophy to decompensated heart failure in humans and animal models 19, 20, 21, 22. Recent evidence indicates that a low apoptotic rate is sufficient to induce a lethal dilated cardiomyopathy [23], suggesting apoptosis as a cause of CHF and inhibition of myocyte apoptosis as a target for new therapies.

Pharmacological studies have suggested that β₁-adrenoceptors and β₂

Cellular mechanisms underlying β₂-adrenoceptor-mediated anti-apoptotic effects

The aforementioned opposing effects of β₁-adrenoceptors and β₂-adrenoceptors on cardiac cell survival and cell death stem largely from their distinct G-protein coupling, particularly β₂-adrenoceptor–G_i coupling. This perception has arisen because inhibition of β₂-adrenoceptor-activated G_i–Gβγ–PI3K–PKB signaling converts β₂-adrenoceptor stimulation from anti-apoptotic to apoptotic [28] and because β₂-adrenoceptor blockade enhances the β₁-adrenoceptor apoptotic effect in a PTX-sensitive manner

Sustained β₁-adrenoceptor stimulation-induced cardiomyocyte apoptosis is mediated by CaMKII signaling independently of PKA

Several early reports point to an essential role of the cAMP–PKA pathway in β₁-adrenoceptor-mediated cell death in the heart 24, 25. Although the cAMP–PKA pathway mediates acute β₁-adrenoceptor-mediated modulation of cardiac excitation–contraction coupling 7, 9, 11, a close inspection of studies to date has revealed no convincing evidence to validate that this is also the case for sustained β₁-adrenoceptor stimulation-evoked apoptosis in myocardium. For example, transgenic overexpression of

β₁-Adrenoceptors, but not β₂-adrenoceptors, promote cardiac hypertrophy via PKA-independent mechanisms

Chronic β₁-adrenoceptor and β₂-adrenoceptor stimulation also manifests opposing effects on cardiac cell growth (hypertrophy). Stimulation of β₁-adrenoceptors, but not β₂-adrenoceptors, causes hypertrophy in cultured neonatal and adult rat cardiac myocytes 46, 47. Moreover, in cultured adult rat ventricular myocytes, β-adrenoceptor stimulation by isoprenaline induces hypertrophic growth only in the presence of β₂-adrenoceptor blockade, suggesting that β₂-adrenoceptor stimulation might inhibit β₁

Epidemiological analysis of β-adrenoceptor subtype polymorphisms in CHF

Human genetic epidemiological studies have shown that enhanced β₁-adrenoceptor activation is a risk factor that aggravates certain cardiac diseases. The naturally occurring Arg389Gly polymorphism of β₁-adrenoceptors, resulting in a sensitized response to agonist stimulation [51], is associated with an increased risk of acute myocardial infarction and a decreased exercise capacity in heart failure 52, 53. As an extreme clinical situation, a double adrenoceptor polymorphism, an α_2C-adrenoceptor

β-Adrenoceptor antagonists as therapy in the prevention or amelioration of CHF

Historically, the development of β-adrenoceptor antagonists has progressed through three different stages, resulting in three distinct generations of β-adrenoceptor antagonists in the treatment of CHF. Although all β-adrenoceptor antagonists can block the signal transduction of β-adrenoceptors, their clinical profiles are markedly different. For example, in patients with CHF, intolerance to the first generation of β-adrenoceptor antagonists was >20% as a result of worsening cardiac contractile

Integrating new perspectives on β-adrenoceptor subtype signaling into potential novel therapies for CHF

The recent success of β-adrenoceptor antagonists in the treatment of CHF leads to a current perception that enhanced β-adrenoceptor stimulation is cardiac detrimental and inhibition of any type of β-adrenoceptor signaling would be expected to produce beneficial effects in patients with CHF. In light of this logic, an increase in βARK1 expression would be expected to improve the function of the failing heart, whereas a reduction in βARK1 would worsen the performance of the failing heart.

Concluding remarks

During the past decade, a wealth of information has been gleaned from classic pharmacological and cell biological approaches and innovative genetic manipulations coupled with clinical analyses in patients with adrenoceptor polymorphisms. Such studies have revealed qualitatively and quantitatively different signaling pathways and opposing functional roles of sustained β₁-adrenoceptor and β₂-adrenoceptor stimulation in the modulation of cardiac remodeling, and therefore in the pathogenesis of

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Although only β₂-adrenergic receptors (βAR) dually couple with stimulatory G protein (G_s) and inhibitory G protein (G_i), inactivation of G_i enhances both β₁AR and β₂AR responsiveness. We hypothesize that G_i restrains spontaneous adenylyl cyclase (AC) activity independent of receptor activation. Subcellular localization of the AC5/6 subtypes varies contributing to the compartmentation of βAR signaling. The primary objectives were to determine: (1) if β₁AR-mediated inotropic responses were dependent upon either AC5 or AC6; (2) if intrinsic G_i inhibition is AC subtype selective and (3) the role of phosphodiesterases (PDE) 3/4 to regulate β₁AR responsiveness. β₁AR-mediated increases in contractile force and cAMP accumulation in cardiomyocytes were measured from wild type, AC5 and AC6 knockout (KO) mice, with or without pertussis toxin (PTX) pretreatment to inactivate G_i and/or after selective inhibition of PDEs 3/4. Noradrenaline potency at β₁ARs was increased in AC6 KO. PDE4 inhibition increased noradrenaline potency in wild type and AC5 KO, but not AC6 KO. PTX increased noradrenaline potency only in wild type but increased the maximal β₁AR response in all mouse strains. PDE3 inhibition increased noradrenaline potency only in AC5 KO that was treated prior with PTX. β₁AR-evoked cAMP accumulation was increased more by PDE4 inhibition than PDE3 inhibition in wild type and AC5 KO that was amplified by G_i inhibition. These data indicate that β₁AR-mediated inotropic responses are not dependent upon either AC5 or AC6 alone. Inactivation of G_i enhanced β₁AR-mediated inotropic responses despite not coupling to G_i, consistent with G_i exerting a tonic receptor independent inhibition upon AC5/6. PDE4 seems the primary regulator of β₁AR signaling through AC6 in wild type. AC6 KO results in a reorganization of β₁AR compartmentation characterized by signaling through AC5 regulated by G_i, PDE3 and PDE4 that maintains normal contractile function.
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Trends in Pharmacological Sciences

Subtype-specific β-adrenoceptor signaling pathways in the heart and their potential clinical implications

Abstract

Section snippets

β2-Adrenoceptor–Gi signaling compartmentalizes β2-adrenoceptor–Gs-mediated cAMP signaling

Opposing roles of β-adrenoceptor subtypes in regulating the fate of cardiomyocytes

Cellular mechanisms underlying β2-adrenoceptor-mediated anti-apoptotic effects

Sustained β1-adrenoceptor stimulation-induced cardiomyocyte apoptosis is mediated by CaMKII signaling independently of PKA

β1-Adrenoceptors, but not β2-adrenoceptors, promote cardiac hypertrophy via PKA-independent mechanisms

Epidemiological analysis of β-adrenoceptor subtype polymorphisms in CHF

β-Adrenoceptor antagonists as therapy in the prevention or amelioration of CHF

Integrating new perspectives on β-adrenoceptor subtype signaling into potential novel therapies for CHF

Concluding remarks

J. Biol. Chem.

J. Biol. Chem.

Biophys. J.

J. Mol. Cell. Cardiol.

J. Biol. Chem.

J. Mol. Cell. Cardiol.

J. Mol. Cell. Cardiol.

J. Biol. Chem.

J. Mol. Cell. Cardiol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Am. Heart J.

Am. Heart J.

J. Am. Coll. Cardiol.

Lancet

J. Mol. Cell. Cardiol.

J. Mol. Cell. Cardiol.

Trends Pharmacol. Sci.

Congestive heart failure: fifty years of progress

Circulation

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

J. Card. Fail

β-Adrenergic signaling in the heart: dual coupling of the β2-adrenergic receptor to Gs and Gi proteins

Sci. STKE

β1-adrenoceptor stimulation and β2-adrenoceptor stimulation differ in their effects on contraction, cytosolic Ca2+, and Ca2+ current in single rat ventricular cells

Circ. Res.

β2-adrenergic receptor actions in neonatal and adult rat ventricular myocytes

Circ. Res.

Localized cAMP-dependent signaling mediates β2-adrenergic modulation of cardiac excitation- contraction coupling

Am. J. Physiol. Heart Circ. Physiol.

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

Circulation

β2-adrenergic cAMP signaling is uncoupled from phosphorylation of cytoplasmic proteins in canine heart

Circulation

β2-adrenoceptor activation by zinterol causes protein phosphorylation, contractile effects and relaxant effects through a cAMP pathway in human atrium

Mol. Cell. Biochem.

Activation of β2-adrenergic receptors hastens relaxation and mediates phosphorylation of phospholamban, troponin I, and C- protein in ventricular myocardium from patients with terminal heart failure

Circulation

Functional coupling of the β2-adrenoceptor to a pertussis toxin-sensitive G protein in cardiac myocytes

Mol. Pharmacol.

Coupling of β2-adrenoceptor to Gi proteins and its physiological relevance in murine cardiac myocytes

Circ. Res.

β2-adrenergic and several other G protein-coupled receptors in human atrial membranes activate both Gs and Gi

Circ. Res.

Age-associated reductions in cardiac β1- and β2-adrenergic responses without changes in inhibitory G proteins or receptor kinases

J. Clin. Invest.

Phosphatidylinositol 3-kinase functionally compartmentalizes the concurrent Gs signaling during β2-adrenergic stimulation

Circ. Res.

Apoptosis in myocytes in end-stage heart failure

N. Engl. J. Med.

Apoptosis in the failing humans heart

N. Engl. J. Med.

Increased cardiomyocyte apoptosis during the transition to heart failure in the spontaneously hypertensive rat

Am. J. Physiol.

A mechanistic role for cardiac myocyte apoptosis in heart failure

J. Clin. Invest.

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

Circulation

β-adrenergic receptor subtypes differentially affect apoptosis in adult rat ventricular myocytes

Circulation

β₂-Adrenoceptor–G_i signaling compartmentalizes β₂-adrenoceptor–G_s-mediated cAMP signaling

Cellular mechanisms underlying β₂-adrenoceptor-mediated anti-apoptotic effects

Sustained β₁-adrenoceptor stimulation-induced cardiomyocyte apoptosis is mediated by CaMKII signaling independently of PKA

β₁-Adrenoceptors, but not β₂-adrenoceptors, promote cardiac hypertrophy via PKA-independent mechanisms

β-Adrenergic signaling in the heart: dual coupling of the β₂-adrenergic receptor to G_s and G_i proteins

β₁-adrenoceptor stimulation and β₂-adrenoceptor stimulation differ in their effects on contraction, cytosolic Ca²⁺, and Ca²⁺ current in single rat ventricular cells

β₂-adrenergic receptor actions in neonatal and adult rat ventricular myocytes

Localized cAMP-dependent signaling mediates β₂-adrenergic modulation of cardiac excitation- contraction coupling

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

β₂-adrenergic cAMP signaling is uncoupled from phosphorylation of cytoplasmic proteins in canine heart

β₂-adrenoceptor activation by zinterol causes protein phosphorylation, contractile effects and relaxant effects through a cAMP pathway in human atrium

Activation of β₂-adrenergic receptors hastens relaxation and mediates phosphorylation of phospholamban, troponin I, and C- protein in ventricular myocardium from patients with terminal heart failure

Functional coupling of the β₂-adrenoceptor to a pertussis toxin-sensitive G protein in cardiac myocytes

Coupling of β₂-adrenoceptor to G_i proteins and its physiological relevance in murine cardiac myocytes

β₂-adrenergic and several other G protein-coupled receptors in human atrial membranes activate both G_s and G_i

Age-associated reductions in cardiac β₁- and β₂-adrenergic responses without changes in inhibitory G proteins or receptor kinases

Phosphatidylinositol 3-kinase functionally compartmentalizes the concurrent Gs signaling during β₂-adrenergic stimulation

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