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The Enigma of ␤2-Adrenergic Receptor Gi Signaling
in the Heart
The Good, the Bad, and the Ugly
Weizhong Zhu, Xiaokun Zeng, Ming Zheng, Rui-Ping Xiao
F
The “Good”: Cardioprotection Induced by
Sustained ␤2AR Stimulation
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our decades ago, it was thought that the cardiac
␤-adrenergic receptor (AR) was ␤1AR, the vascular/
bronchial counterpart was ␤2AR, and that ␤2AR was
either nonexistent or nonfunctional in myocardium.1 In the heart,
stimulation of ␤1AR leads to PKA-dependent phosphorylation
of a set of Ca2⫹ regulatory proteins, including sarcolemmal
L-type Ca2⫹ channels, sarcoplasmic reticulum (SR) Ca2⫹-release
channels (ryanodine receptors), SR Ca2⫹-ATPase (SERCA) and
its regulator phospholamban (PLB), and some myofilament
proteins, resulting in positive inotropic, lusitropic, and chronotropic effects. However, over the past decade, compelling
evidence has shown that the ␤2AR subtype is expressed in the
heart and its signaling and functionalities markedly differ from
those evoked by the closely related ␤AR subtype, the ␤1AR.
Unlike ␤1AR, ␤2AR couples dually to Gs and Gi proteins; the
␤2AR-Gi signaling pathway plays a crucial role in cardioprotection against apoptotic death of myocytes in culture and in vivo
(the “good”), while attenuating the ␤2AR-Gs–mediated inotropic
response (the “bad”) (Figure).2 Now, in the current issue of
Circulation Research, He et al revealed one “ugly” facet of the
␤2AR-Gi signaling in a canine heart failure model.3 They
demonstrated that in the failing heart, activation of ␤2AR
dampens the ability of ␤1AR, the primary cardiac subtype, to
stimulate ICa,L, thus resulting in an overall dysfunction of ␤AR
inotropic response in the failing heart (Figure).3 Specifically, the
effect of ␤AR stimulation with a nonselective agonist, isoproterenol (ISO), on ICa,L is strikingly diminished in cardiomyocytes
from canine failing heart, but can be revived by disruption of Gi
function with pertussis toxin (PTX) or ␤2AR blockade with ICI
118 551.3 These findings highlight that an alteration in the status
of the ␤2AR-Gi coupling can dictate the overall outcome of
cardiac ␤AR signaling under some pathological circumstances.
Thus, this enigmatic, multifaceted ␤2AR-Gi signaling pathway
might bear important pathogenic and therapeutic implications.
A large body of evidence gleaned from pharmacological and
mouse genetic studies has revealed opposing contributions of
sustained ␤1AR and ␤2AR stimulation in regulating the fate of
cardiomyocytes. Whereas sustained ␤1AR stimulation promotes
apoptotic death of cardiomyocytes, sustained stimulation of
␤2AR protects myocytes against a wide range of apoptotic
insults. For instance, agonist-induced ␤2AR stimulation prevents
catecholamine-, hypoxia-, or reactive oxygen species (ROS)induced apoptotic death in both neonatal and adult rat cardiomyocytes.4 – 6 Moreover, in adult mice lacking the native ␤2AR,
stimulation of the native ␤1AR by catecholamine causes overtly
exaggerated cardiomyopathy, myocyte apoptosis, and more
severe heart failure relative to wild-type control animals.7 In
contrast, selective activation of ␤2AR by fenoterol for 8 weeks
exerts a clear antiapoptotic effect and improves cardiac performance in a myocardial infarction–induced rat heart failure
model.8 These in vivo studies have provided evidence that ␤2AR
stimulation exerts a cardiac protective effect in response to
elevated circulating catecholamine levels or myocardial
infarction.
The cardiac protective effect of persistent ␤2AR signaling is
largely mediated by ␤2AR-Gi coupling, which, in turn, activates
a cell survival pathway sequentially involving Gi␤␥, PI3K, and
Akt. First, ␤2AR blockade enhances ␤1AR-induced apoptosis in
cultured adult rat myocytes in a PTX-sensitive manner, suggesting the ␤2AR protective effect is Gi-dependent.4 Second, ␤2AR,
but not ␤1AR, activates a Gi-G␤␥-PI3K-Akt cell survival signaling pathway6,9, and inhibition of this pathway abolishes the
ability of ␤2AR to block hypoxia- and ROS-induced myocyte
apoptosis.6 Thus, the ␤2AR-Gi- G␤␥-PI3K-Akt signaling cascade
not only counteracts ␤AR-induced apoptosis and but also protects cardiomyocytes against other apoptotic stimuli.
The “ Bad” or “Ugly”: ␤2AR-coupled Gi Negates
␤1AR- and ␤2AR-Mediated Contractile Support in
the Failing Heart
The opinions expressed in this editorial are not necessarily those of the
editors or of the American Heart Association.
From the Laboratory of Cardiovascular Science (W.Z., X.Z., R.-P.X.),
National Institute of Aging, National Institutes of Health, Baltimore, Md;
and The Institute of Molecular Medicine (M.Z., R.-P.X.), Peking University, Beijing, China.
Correspondence to Rui-Ping Xiao, MD, PhD, Laboratory of Cardiovascular Science, Gerontology Research Center, NIA, NIH, 5600 Nathan
Shock Drive, Baltimore, MD 21224. E-mail [email protected]
(Circ Res. 2005;97:507-509.)
© 2005 American Heart Association, Inc.
Although beneficial in terms of cardiac protection, the ␤2AR
protective effect comes at the cost of compromised contractile
support. Previous studies have demonstrated that the ␤2AR-Gi
functionally restricts the ␤2AR-Gs–mediated cAMP/PKA signaling to subsarcolemmal microdomain in the vicinity of L-type
Ca2⫹ channels, thus preventing the Gs-PKA mediated phosphorylation of some key target proteins in SR membrane and
intracellular contractile myofilaments, blunting the positive inotropic and lusitropic effects.10 –13 Activation of PI3K, an important downstream event of the ␤2AR-Gi signaling, confines and
Circulation Research is available at http://circres.ahajournals.org
DOI: 10.1161/01.RES.0000184615.56822.bd
507
508
Circulation Research
September 16, 2005
Cross Inhibition of ␤1AR-mediated activation of L-type Ca2⫹ currents (ICa,L) and
positive inotropic effect by enhanced
␤2AR-Gi signaling in the failing heart. The
␤2AR-Gi signaling also protects cardiomyocytes against ␤1AR-mediated apoptosis and maladaptive remodeling via
suppressing PKA-independent stimulation of ICa,L and CaMKII (PTX indicates
pertussis toxin; PKA, protein kinase A;
CaMKII, Ca2⫹/calmodulin- dependent
protein kinase II). In addition, in the normal heart but not the failing heart, heterodimerization of ␤1AR and ␤2AR optimizes ␤-adrenergic modulation of
cardiac contractility likely via reducing
␤2AR-Gi coupling.
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minimizes the concurrent ␤2AR-Gs– evoked cAMP/PKA signaling.14 In the failing heart, an upregulation of Gi15 and a selective
downregulation of ␤1AR16 are often associated with enhanced
␤2AR-Gi signaling and reduced myocardial contractile response
to both ␤1AR and ␤2AR stimulation. Importantly, inhibition of
the Gi signaling pathway with PTX restores the diminished ␤AR
inotropic response in a variety of heart failure models, including
a spontaneous hypertensive rat heart failure model,17 a myocardial infarction rat heart failure model,18 and myocytes from
failing human hearts.19 Furthermore, in failing porcine and
mouse hearts or cardiomyocytes, inhibition of ␤AR-targeted
PI3K, the major downstream mediator the Gi signaling, improves the contractile function of the failing myocardium.20,21
Now, He and colleagues demonstrate a cross-inhibition of
␤1AR-mediated stimulation of ICa,L by the ␤2AR-Gi signaling.3
Similarly, the ␤2AR-Gi signaling largely inhibits ␤1AR-induced
positive inotropic effect in adult rat cardiomyocytes moderately
overexpressing Na⫹/Ca2⫹ exchanger proteins.22 Collectively,
these studies suggest that reinforcement of ␤2AR-Gi signaling is
a hallmark of the failing heart and is critically involved in heart
failure–associated dysfunction or desensitization of both ␤AR
subtypes.
The Cell Logic of Multifaceted ␤2AR-Gi Signaling
At the first glance, inhibition of the ␤1AR-mediated stimulation
of ICa,L and, consequentially, the contractile response by ␤2ARcoupled Gi might paint ␤2AR stimulation as the “bad guy” in the
context of heart failure. It is, however, noteworthy that sustained
␤1AR stimulation induces myocyte apoptosis and positive inotropic effect mainly via PKA-independent stimulation of L-type
Ca2⫹ channels and resultant activation of CaMKII in adult
mouse and rat cardiomyocytes (Figure).23,24 Inhibition of ICa,L or
CaMKII can effectively protect the cultured cardiomyocytes
from ␤1AR-induced apoptotic death.23 In contrast, overexpression of the L-type channel (␣1C) causes severe cardiac hypertrophy and apoptosis.25 Recent in vivo studies have further
confirmed that inhibition of CaMKII substantially prevents
cardiac maladaptive remodeling from excessive ␤AR stimulation and myocardial infarction and markedly improves cardiac
function (Figure).26 In light of these observations, we envision
that the inhibitory effect of the ␤2AR-Gi signaling on ␤1ARmediated activation of ICa,L and resultant CaMKII may represent
an intrinsic cardiac protective mechanism, acting as a “friend”
rather than a “foe,” to protect the heart against apoptosis and
maladaptive remodeling in response to chronic catecholamine
stimulation. Thus, the apparent “bad” or “ugly” behavior might
be an overreaction of the defense mechanism; appropriately
tipping the balance might be able to bring out the “good” nature
of ␤2AR-Gi signaling to benefit the struggling heart.
Potential Mechanisms Underlying the
Gi-Dependent Crosstalk of ␤AR Subtypes
The exact mechanism underlying the cross-inhibition of ␤1AR
function by the ␤2AR-Gi signaling remains elusive. There are
several candidate mechanisms, including the ␤2AR-Gi signaling–mediated direct suppression of adenylyl cyclase activity or
activation of PI3K. With respect to the latter, it has been shown
that activation of PI3K inhibits ICa,L in normal adult rat cardiomyocytes.27 More importantly, inhibition of membrane-targeted
PI3K activity ameliorates cardiac dysfunction and improves
survival in multiple heart failure models.20,21
Alternatively, we have recently demonstrated that ␤1AR and
␤2AR are able to form heterodimers in adult mouse cardiomyocytes and HEK 293 cells.28,29 Specifically, in cardiomyocytes,
the heterodimeric receptors exhibit altered ligand binding profiles, enhanced signaling efficiency in regulating myocyte
cAMP production and contractility, and suppressed ␤2AR spontaneous activity in the absence of agonist stimulation, thus
optimizing ␤-adrenergic regulation of cardiac contractility (Figure).28 Interestingly, heterodimerization between ␤1AR and
␤2AR inhibits the agonist-promoted internalization of ␤2AR and
its ability to activate the Gi-ERK1/2 MAPK signaling pathway
in HEK 293 cells.29 Similarly, whereas either ␤2AR or ␤3AR
alone couples to both Gs and Gi proteins, the ␤2AR-␤3AR
heterodimer is unable to activate Gi signaling.30 Thus, alterations
in the status of oligomerization of GPCRs from the same or
different families may lead to changes in the selectivity and
specificity of G protein coupling of those receptors, thereby
altering their signaling and functional features, perhaps also
raising important therapeutic considerations.
The heart failure–associated decrease in the ratio of ␤1AR to
␤2AR,3,16 in conjunction with changes in cardiomyocyte morphology and membrane integrity, might interfere with the
heterodimerization of the remaining ␤ARs, thus allowing the
␤2AR to better couple to Gi proteins. The enhanced Gi signaling
inhibits ␤1AR-mediated increases in ICa,L and contractility, per-
Zhu et al
haps most importantly, ameliorates ␤1AR-evoked maladaptive
remodeling and loss of cardiomyocytes (Figure). These hypotheses merit future investigation.
In summary, it is reasonable to speculate that the selective
downregulation of ␤1AR and the upregulation of ␤2AR-coupled
Gi signaling in the functionally compensated hypertrophied heart
may represent salutary cardiac adaptation, which may protect
myocytes against apoptosis and maladaptive remodeling and
consequently slow the progression of cardiomyopathy and contractile dysfunction. However, exaggerated ␤2AR-Gi signaling
blunts the Gs-mediated stimulation of ICa,L and contractile support, thus contributing to the contractile defect of the failing
heart despite of its antiapoptotic effect. Thus, restoration of the
Yin and Yang balance of ␤2AR-coupled Gi and Gs signaling
cascades may open a novel therapeutic avenue for the treatment
of heart failure.
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Acknowledgments
This work is supported by National Institutes of Health intramural
research grant (to Z.W.Z., X.Z., and R.P.X.), and in part by Chinese
National Key Project 973 (G2000056906) and Chinese Young
Investigator Award (30225036). The authors thank Dr H. Cheng for
critical comments and discussions.
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The Enigma of β2-Adrenergic Receptor Gi Signaling in the Heart: The Good, the Bad, and
the Ugly
Weizhong Zhu, Xiaokun Zeng, Ming Zheng and Rui-Ping Xiao
Circ Res. 2005;97:507-509
doi: 10.1161/01.RES.0000184615.56822.bd
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