β-Adrenergic Receptor Subtype Signaling in the Heart: from Bench to the Bedside

doi:10.1016/B978-0-12-384921-2.00009-4

Current Topics in Membranes

Volume 67, 2011, Pages 191-204

https://doi.org/10.1016/B978-0-12-384921-2.00009-4 Get rights and content

Publisher Summary

This chapter discusses the β-adrenergic receptor (βAR) subtype signaling in the heart. The stimulation of βAR, a prototypical member of G protein-coupled receptor (GPCR) superfamily, is broadly involved in metabolic regulation, growth control, muscle contraction, cell survival, and cell death. The major βAR subtypes—β₁AR and β₂AR—couple to distinct G proteins and differentially regulate cardiac function and remodeling. Three major discoveries have marked the recent research line with respect to βAR subtype-specific signal transduction. Heart failure (HF) is a complex clinical syndrome featured by extensive abnormalities in the βAR system, including elevated circulating catecholamine levels, selective down regulation and desensitization of β₁AR, and increased β₂AR-coupled G_i signaling. In particular, the enhanced G_i signaling negates β₁AR- as well as β₂AR-mediated contractile response, thus contributing to the pathogenesis of HF. Recent translational studies support the concept that inhibition of the G_i signaling or selective β₂AR-G_s stimulation with fenoterol markedly improves cardiac remodeling and the function of the failing heart.

Section snippets

Overview

Stimulation of β-adrenergic receptor (βAR), a prototypical member of G protein-coupled receptor (GPCR) superfamily, is broadly involved in metabolic regulation, growth control, muscle contraction, cell survival, and cell death. The major βAR subtypes, β₁AR and β₂AR, couple to distinct G proteins and differentially regulate cardiac function and remodeling. Three major discoveries have marked the recent research line with respect to βAR subtype-specific signal transduction. These include: (1)

Prolonged Stimulation of β₁AR Triggers Cardiomyocyte Apoptosis and Maladaptive Cardiac Remodeling

The persistent stimulation of β₁AR and β₂AR exhibits distinct outcomes under certain pathological circumstances such as HF. Specifically, persistent stimulation of β₁AR in mouse cardiomyocytes lacking β₂AR (β₂AR knockout or β₁β₂ double knockout) in conjunction with adenoviral gene transfer of β₁AR triggers cardiomyocyte apoptosis by a CaMKII-dependent mechanism that is independent of PKA signaling (Zhu et al., 2003). Furthermore, β₁AR-activated CaMKII signaling, but not the PKA pathway, is

Mechanisms Underlying β₂AR-Coupled G_i Signaling

The classic view on βAR-coupled G_s signaling involves an agonist-induced change in the receptor conformation that causes the activation of the G_s protein, leading the formation of the second messenger, cAMP, which activates PKA and downstream signaling. The termination of this cascade occurs when GPCR kinases (GRKs) and the second messenger kinase, PKA, phosphorylate the activated receptor and promote the binding of β-arrestins which sterically block the coupling of G_s to the receptor. It is

RGS2-Mediated Termination of β₂AR-coupled G_i Signaling and Its Potential Pathogenic and Therapeutic Implications

As discussed above, in contrast to the βAR-G_s signaling, the β₂AR-G_i signaling is enhanced by PKA- and GRK2-mediated phosphorylation of the receptor (Daaka et al., 1997, Hausdorff et al., 1990, Liu et al., 2009). The next fundamental question is what is the mechanism underlying the termination of the β₂AR-G_i signaling. In this regard, it has been shown that upon GPCR activation, GDP is exchanged for GTP on the Gα subunit, resulting in dissociation of the Gα from Gβγ subunits and the activation

Ligand-Directed Selective Activation of β₂AR-Coupling to G_s or G_i

It is now well established that any given ligand for a GPCR does not simply possess a single defined efficacy. Rather, a ligand possesses multiple efficacies, depending on the specific down-stream signal transduction pathway analyzed. This diversity reflects ligand-specific GPCR conformations and is often referred to as “Functional Selectivity.” It has been known for a century that stereoisomers of catecholamines differ in their potency and efficacy. However, the molecular basis for differences

Development of β₂AR Agonists into new Drugs for the Treatment of Heart Failure

A hallmark of HF is the desensitization of βAR signaling, characterized by downregulation of βAR, reduced signaling efficient of remaining receptors, increased G_i signaling, and elevated circulating catecholamine levels. However, HF-associated loss of βAR is selective for β₁AR, with little change in β₂AR. Previous studies have demonstrated that (a) β₂AR dually couples to the G_i and the G_s signaling pathways in the heart with the G_i coupling negating the G_s-mediated contractile response, whereas

Future Perspective

Studies over the past decade have greatly enriched our understanding of βAR subtype-specific signal transduction and biological functions in normal and disease conditions, but also raised many perplexing questions regarding β₂AR signaling and the potential interaction between βAR subtypes in the failing heart. First, if the β₂AR-coupled G_i signaling is inactive during β₂AR stimulation with R,R-isomers of fenoterol and its derivatives, what is the mechanism underlying their prosurvival effects

References (67)

L.S. Bernstein et al.
RGS2 binds directly and selectively to the M1 muscarinic acetylcholine receptor third intracellular loop to modulate Gq/11alpha signaling
J Biol Chem
(2004)
J.D. Bisognano et al.
Myocardial-directed overexpression of the human β₁-adrenergic receptor in transgenic mice
J Mol Cell Cardiol
(2000)
D.J. Choi et al.
Mechanism of β-adrenergic receptor desensitization in cardiac hypertrophy is increased β-adrenergic receptor kinase
J Biol Chem
(1997)
C. Hague et al.
Selective inhibition of alpha1A-adrenergic receptor signaling by RGS2 association with the receptor third intracellular loop
J Biol Chem
(2005)
J. Hao et al.
Regulation of cardiomyocyte signaling by RGS proteins: Differential selectivity towards G proteins and susceptibility to regulation
J Mol Cell Cardiol
(2006)
N.C. Lai et al.
Activation of cardiac adenylyl cyclase expression increases function of the failing ischemic heart in mice
J Am Coll Cardiol
(2008)
R. Liu et al.
Agonist dose-dependent phosphorylation by protein kinase A and G protein-coupled receptor kinase regulates β₂-adrenoceptor coupling to G_i proteins in cardiomyocytes
J Biol Chem
(2009)
G. Rengo et al.
GRK2 as a novel gene therapy target in heart failure
J Mol Cell Cardiol.
(2011)
M. Sato et al.
Loss of β-adrenoceptor response in myocytes overexpressing the Na⁺/Ca²⁺-exchanger
J Mol Cell Cardiol
(2004)
X. Wang et al.
RGS5, RGS4, and RGS2 expression and aortic contractibility are dynamically co-regulated during aortic banding-induced hypertrophy
J Mol Cell Cardiol
(2008)

T. Wieland et al.

Regulators of G protein signalling: A spotlight on emerging functions in the cardiovascular system

Curr Opin Pharmacol

(2007)

R.P. Xiao et al.

Na⁺/Ca²⁺ exchange linking β₂-adrenergic G_i signaling to heart failure: Associated defect of adrenergic contractile support

J Mol Cell Cardiol

(2004)

R.P. Xiao et al.

β₂-adrenergic receptor-stimulated increase in cAMP in rat heart cells is not coupled to changes in Ca²⁺ dynamics, contractility, or phospholamban phosphorylation

J Biol Chem

(1994)

R.P. Xiao et al.

Subtype-specific α₁- and β-adrenoceptor signaling in the heart

Trends Pharmacol Sci

(2006)

S. Zhang et al.

RGS3 and RGS4 are GTPase activating proteins in the heart

J Mol Cell Cardiol

(1998)

W. Zhang et al.

Selective loss of fine tuning of Gq/11 signaling by RGS2 protein exacerbates cardiomyocyte hypertrophy

J Biol Chem

(2006)

M.X. Zou et al.

RGS2 is upregulated by and attenuates the hypertrophic effect of alpha1-adrenergic activation in cultured ventricular myocytes

Cell Signal

(2006)

I. Ahmet et al.

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

Circulation

(2004)

I. Ahmet et al.

Cardioprotective and survival benefits of long-term combined therapy with β₂-adrenoreceptor (AR) agonist and beta1 AR blocker in dilated cardiomyopathy postmyocardial infarction

J Pharmacol Exp Ther

(2008)

I. Ahmet et al.

Pharmacological stimulation of β₂-adrenergic receptors (β₂AR) enhances therapeutic effectiveness of β₁AR blockade in rodent dilated ischemic cardiomyopathy

Heart Fail Rev

(2005)

C.L. Antos et al.

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

Circ Res

(2001)

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 beta 1-receptor down-regulation in heart failure

Circ Res

(1986)

K. Chakir et al.

Mechanisms of enhanced β-adrenergic reserve from cardiac resynchronization therapy

Circulation

(2009)

K. Chakir et al.

RGS2 Is a primary terminator of β₂-adrenergic receptor-mediated G_i signaling

J Mol Cell Cardiol

(2011)

A. Chesley et al.

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

Circ Res

(2000)

Y. Daaka et al.

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

Nature

(1997)

S. Engelhardt et al.

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

Proc Natl Acad Sci USA

(1999)

T. Eschenhagen et al.

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

Circ Res

(1992)

W.P. Hausdorff et al.

Two kinases mediate agonist-dependent phosphorylation and desensitization of the β₂-adrenergic receptor

Symp Soc Exp Biol

(1990)

T.E. Hebert

Anti-beta1AR antibodies in dilated cardiomyopathy: Are these a new class of receptor agonists?

Cardiovasc Res

(2007)

S.P. Heximer et al.

Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice

J Clin Invest

(2003)

S.P. Heximer et al.

RGS2/G0S8 is a selective inhibitor of Gqalpha function

Proc Natl Acad Sci USA

(1997)

Cited by (16)

Endocrine regulation of phospholipase as a therapeutic target for cardiovascular diseases
2023, Phospholipases in Physiology and Pathology: Volumes 1-7
Binding of specific receptors on the cell membrane activates specific phospholipases. Based on the site of action of cleavage at phospholipid positions, phospholipase are classified into four different types of phospholipases, namely PLA, PLB, PLC, and PLD. Phospholipids have a phosphate group, two alcohols, and one or two fatty acids as part of their general structure. Atrial cardiomyocytes, ventricular cardiomyocytes, endothelial cells (ECs), fibroblasts (FBs), pericytes, smooth muscle cells (SMCs), immune cells (myeloid and lymphoid), adipocytes, mesothelium cells, and neuronal cells are among several cell types found in cardiac tissue. The majority of the cells that reside in heart tissues are cardiomyocytes. The lipid mediators prostaglandin and leukotriene, which are eicosanoid derivatives of arachidonic acid (AA), play key roles in inflammation. The cytosolic Ca²⁺ concentration is regulated by the intracellular storage sarcoplasmic reticulum, which controls Ca²⁺ release. Eicosanoids that are produced from AA by the enzyme PLA2 trigger the release of prostaglandins and leukotrienes. In the canine heart (sarcolemma fraction), it was found that 21% of AA and 75% of plasmenyl choline and plasmenyl ethanolamine PLC regulates the cytosolic release of Ca²⁺ ions from Ca²⁺ ions channels present in the intercellular sarcoplasmic reticulum. Each individual compound obtained during phospholipase activity plays a different biological role. A percentage of plasmalogens are tissue-specific and differ among various animal species. This chapter is an attempt to outline the role of phospholipase in cardiovascular diseases (CVDs) and their endocrine regulatory mechanism, along with the discovery of phospholipase-based drugs and mechanism of action in CVDs.
Expression of the β1-adrenergic receptor (ADRB1) gene in the myocardium and β-adrenergic reactivity of the body in patients with a history of myocardium infraction
2022, Gene
Citation Excerpt :
In a healthy human heart, the ratio of β1-ARs to β2-ARs is approximately 4:1, and the expression of β3-ARs is minimal (Myagmar et al., 2017). Β1-ARs directly affect on intracardiac hemodynamic and the ability of the heart to tolerate physical activity by regulating its inotropic and chronotropic functions (Ranade et al., 2002, Zhu et al., 2011). They are encoded by the ADRB1 gene (MIM 109630) located on chromosome 10 (10q25.3) (Frielle et al., 1987, Yang-Feng et al., 1990).
β1-adrenergic receptors (β1-AR) directly affect on intracardiac hemodynamic and the ability of the heart to tolerate physical activity by regulating its inotropic and chronotropic functions. Severe hypersympathicotonia, specific to coronary artery disease (CAD) and chronic heart failure (HF), leads to impaired functioning of β1-AR. The aim of this research was to assess the expression level of the β1-AR ADRB1 gene in the myocardium, to evaluate the β-adrenergic reactivity of the membrane (β-ARM) of erythrocytes, and to analyze the association of these parameters with myocardial contractile dysfunction in patients with a myocardial infarction (MI) in the past and without it. The study included 126 patients with chronic CAD. Among the patients, 55.6 % had a history of MI at least 6 months ago. The expression of the ADRB1 gene was assessed using real-time polymerase chain reaction. With this purpose, we isolated RNA from the right atrial appendage, which was excised when a heart–lung machine was connected during a planned coronary bypass surgery. β-ARM was evaluated in 57 patients. This method is based on the fact of inhibition of hemolysis of erythrocytes, placed in a hyposmotic medium, in the presence of a β-blocker. Within the whole sample of patients, the expression of the ADRB1 gene is comparable in different functional classes of HF. There was no linear correlation between the expression of the ADRB1 gene and left ventricle ejection fraction (LVEF). In patients with a history of MI, the expression of the ADRB1 gene was elevated when compared to a group of patients without MI (p = 0.017). Patients with a history of MI had higher values of β-ARM than those without MI (p = 0.017). The reverse correlation between β-ARM and LVEF (r = -0,570, p = 0,002) was revealed in the group of patients without MI but not in the group of patients with a history of MI (r = -0,137, p = 0,479). In the sample of patients with chronic CAD, in the myocardium of subjects with a history of MI, the relative expression of ADRB1 gene was higher compared to the group of patients without MI. In patients with different functional classes (FC) of HF and with different ejection fraction, both with MI and without it, ADRB1 gene expression was comparable. In the group of patients with a history of MI, an increase in β-ARM was observed, i.e. decrease in the number or sensitivity of β-AR. Among patients without MI, an inverse correlation was found between β-ARM and LVEF.
Palmitoylation and G-protein coupled receptors
2022, Progress in Molecular Biology and Translational Science
Citation Excerpt :
The β and α adrenergic receptors (AR), represent the two subfamilies of adrenergic receptors (AR). The β-AR subfamily consists of the three subtypes: β1, β2, β3 and β4 being controversial.64,65 The first three receptors are class A GPCRs and interact with different subunits of GαI and/or Gαs via their third inner loop.66
More and more it is being appreciated that not all GPCRs are the same, sub-populations of GPCRs exist within a cell and function differently than others. The question is, how does one regulate a given sub-population? One way is through the addition of post-translational modifications to G-protein coupled receptors (GPCR). This process has long been known to occur and play a role in trafficking, pharmacology and ultimately function. This chapter will focus on one particular modification, that of S-palmitoylation, and its impact on GPCR function. We will discuss the history of this modification on these receptors and the connection with disease. We will highlight several examples from the literature of where palmitoylation impacts GPCR function.
Novel anticancer drugs related to cardiotoxicity
2022, Cardiovascular Toxicity and Therapeutic Modalities Targeting Cardio-oncology: From Basic Research to Advanced Study
Cardiotoxicity is one of the most detrimental effects of cancer treatment. It causes substantial morbidity and mortality. Most cancer treatments adversely affect the cardiovascular system, leading to heart failure with ventricular systolic dysfunction. There are several other toxic effects, including hypertension, thromboembolism, pericardial disease, arrhythmia, and myocardial ischemia. Cancer therapy-induced cardiomyopathy was predominantly associated with higher doses of anthracyclines, which result in permanent cellular damage. Several drugs that are commonly used for cardioprotection may even increase the risk of cancer. Since G-protein-coupled receptors (GPCRs) are target of 40% of clinically used drugs, here we discuss the newly identified cardioprotective agents that bind GPCRs of adrenalin, adenosine, melatonin, ghrelin, galanin, apelin, and cannabidiol. Further studies are needed to examine these GPCRs as a potential target for the treatment of heart failure induced by anticancer drugs.
Danhong injection attenuates isoproterenol-induced cardiac hypertrophy by regulating p38 and NF-κb pathway
2016, Journal of Ethnopharmacology
Citation Excerpt :
The two major βAR, β1-and β2-AR, are widely studied now. β-ARs have different, even opposing effects on the process of CH, since they can bind to heterotrimeric guanosine triphosphate binding proteins (G protein) such as the stimulatory G protein (Gs) and the inhibitory G protein (Gi) (Zhu et al., 2011). β1-AR is reported to couple with Gs, which activate the AC-cAMP- PKA-Ca2+signaling pathways.
Danhong injection (DHI), derived from Rhizoma Salviae Miltiorrhizae (Salvia miltiorrhiza Bge., Labiatae, Danshen in Chinese) and Flos Carthami (Carthamus tinctorius L., Compositae, Salvia militiorrhiza Bunge), is an extensively-used Chinese material standardized clinical product for treatment of cardiovascular diseases.
Cardiac hypertrophy (CH) is an adaptive response of cardiomyocytes. Long-lasting cardiac hypertrophy results in the loss of compensation by cardiomyocytes which could ultimately develop into heart failure. In the present study, we aimed to investigate the effect and exact mechanisms of DHI on isoproterenol (ISO)-induced CH.
H9c2 cells and male Wistar rats were stimulated by ISO in the present study to establish CH models in vitro and in vivo. CCk-8 assay, Western blot, real time-polymerase chain reaction (RT-PCR), electrophoretic mobility shift assay (EMSA) and Echocardiography were used in the present study.
DHI significantly attenuated ISO-induced CH of H9c2 cells (p<0.01). DHI decreased ISO-induced atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) elevation both at the mRNA and protein levels (p<0.05 and p<0.01, respectively). Western blot showed that DHI down-regulated the phosphorylation of p38. Furthermore, we found that DHI inhibited the nuclear translocation and activation of NF-κb. Echocardiography from ISO-induced CH rats showed that DHI significantly decreased left ventricle (LV) mass, the thickness of the LV end-systolic posterior wall (LVPWs), and the LV end-diastolic posterior wall (LVPWd) elevated by ISO (p<0.01 and p<0.05, respectively).
These data demonstrate that DHI might exert anti-cardiac hypertrophic effects by regulating p38 and NF-κb pathway.
β2-AR-induced Her2 transactivation mediated by Erbin confers protection from apoptosis in cardiomyocytes
2013, International Journal of Cardiology
Citation Excerpt :
Chronic exposure to catecholamine is associated with cardiomyocyte apoptosis, which contributes to the pathophysiology of myocardial failure [22]. It has been proposed that activation of β1-AR is directly proapoptotic via a Gs-mediated, PKA-dependent mechanism, whereas β2-AR-mediated signaling improves cardiac contractility and protects cardiomyocytes from apoptosis caused by chronic β1-AR stimulation [23]. It has also been reported that ERK signaling pathway plays an important role in the regulation of cardiomyocyte apoptosis [1].
Her2 and β2-adrenergic receptor (β2-AR) can form a heterocomplex in cardiomyocytes and agonists can induce Her2 transactivation, which is important for cardiovascular homeostasis. The scaffolding molecules that mediate β2-AR/Her2 interaction are currently unknown. Erbin, a PDZ domain-containing protein is a binding partner of Her2. The C-terminus of β2-AR harbors a PDZ domain-binding motif. Hypothesis of this study is that Erbin may organize the assembly of β2-AR/Her2 complex.
The interaction among β2-AR, Her2 and Erbin was investigated in COS-7, HEK-293 and H9c2 cells and rat brain and heart tissues by coimmunoprecipitation. The β2-AR binding region of Erbin was identified by utilizing the Erbin deletion mutants. The functional significance of Erbin in cardiomyocytes was determined by Erbin silencing, contraction frequency measurement and cellular apoptosis assays.
Erbin was able to form a complex with both exogenous and endogenous β2-AR and Her2 in the presence of isoproterenol (ISO). Deletion of the Erbin LRR domain did not affect its binding to β2-AR and Her2, whereas lacking of the PDZ domain lost the ability of Erbin. Silencing of Erbin greatly abrogated ISO-induced activation of ERK. The treatment of H9c2 cells transfected with the Erbin siRNA with ISO caused severe cell apoptosis. Knock-down of Erbin expression in primary neonatal rat cardiomyocytes led to a remarkable reduction of the beating frequency after ISO stimulation.
Erbin mediates catecholamine-induced β2-AR/Her2 complexation and promotes catecholamine-induced activation of ERK signaling in cardiomyocytes, conferring protection of cardiomyocytes from apoptosis induced by chronic catecholamine stimulation.

View all citing articles on Scopus

View full text

Chapter 9 - β-Adrenergic Receptor Subtype Signaling in the Heart: from Bench to the Bedside

Publisher Summary

Section snippets

Overview

Prolonged Stimulation of β1AR Triggers Cardiomyocyte Apoptosis and Maladaptive Cardiac Remodeling

Mechanisms Underlying β2AR-Coupled Gi Signaling

RGS2-Mediated Termination of β2AR-coupled Gi Signaling and Its Potential Pathogenic and Therapeutic Implications

Ligand-Directed Selective Activation of β2AR-Coupling to Gs or Gi

Development of β2AR Agonists into new Drugs for the Treatment of Heart Failure

Future Perspective

J Biol Chem

J Mol Cell Cardiol

J Biol Chem

J Biol Chem

J Mol Cell Cardiol

J Am Coll Cardiol

J Biol Chem

J Mol Cell Cardiol.

J Mol Cell Cardiol

J Mol Cell Cardiol

Curr Opin Pharmacol

J Mol Cell Cardiol

J Biol Chem

Trends Pharmacol Sci

J Mol Cell Cardiol

J Biol Chem

Cell Signal

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

Circulation

Cardioprotective and survival benefits of long-term combined therapy with β2-adrenoreceptor (AR) agonist and beta1 AR blocker in dilated cardiomyopathy postmyocardial infarction

J Pharmacol Exp Ther

Pharmacological stimulation of β2-adrenergic receptors (β2AR) enhances therapeutic effectiveness of β1AR blockade in rodent dilated ischemic cardiomyopathy

Heart Fail Rev

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

Circ Res

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 beta 1-receptor down-regulation in heart failure

Circ Res

Mechanisms of enhanced β-adrenergic reserve from cardiac resynchronization therapy

Circulation

RGS2 Is a primary terminator of β2-adrenergic receptor-mediated Gi signaling

J Mol Cell Cardiol

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

Circ Res

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

Nature

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

Proc Natl Acad Sci USA

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

Circ Res

Two kinases mediate agonist-dependent phosphorylation and desensitization of the β2-adrenergic receptor

Symp Soc Exp Biol

Anti-beta1AR antibodies in dilated cardiomyopathy: Are these a new class of receptor agonists?

Cardiovasc Res

Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice

J Clin Invest

RGS2/G0S8 is a selective inhibitor of Gqalpha function

Proc Natl Acad Sci USA

Prolonged Stimulation of β₁AR Triggers Cardiomyocyte Apoptosis and Maladaptive Cardiac Remodeling

Mechanisms Underlying β₂AR-Coupled G_i Signaling

RGS2-Mediated Termination of β₂AR-coupled G_i Signaling and Its Potential Pathogenic and Therapeutic Implications

Ligand-Directed Selective Activation of β₂AR-Coupling to G_s or G_i

Development of β₂AR Agonists into new Drugs for the Treatment of Heart Failure

Cardioprotective and survival benefits of long-term combined therapy with β₂-adrenoreceptor (AR) agonist and beta1 AR blocker in dilated cardiomyopathy postmyocardial infarction

Pharmacological stimulation of β₂-adrenergic receptors (β₂AR) enhances therapeutic effectiveness of β₁AR blockade in rodent dilated ischemic cardiomyopathy

β₁- and β₂-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: Coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor down-regulation in heart failure

RGS2 Is a primary terminator of β₂-adrenergic receptor-mediated G_i signaling

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

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

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

Two kinases mediate agonist-dependent phosphorylation and desensitization of the β₂-adrenergic receptor