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(Circulation Research. 1999;85:1092.)
© 1999 American Heart Association, Inc.

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Recent Advances in Cardiac ß₂-Adrenergic Signal Transduction

Rui-Ping Xiao, Heping Cheng, Ying-Ying Zhou, Meike Kuschel, Edward G. Lakatta

From the Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, Md.

Correspondence to Rui-Ping Xiao, MD, PhD, Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Dr, Baltimore, MD 21224. E-mail XiaoR{at}grc.nia.nih.gov

	Abstract

Top Abstract Overview: Myocardial {beta}... Distinct {beta}-AR Subtype... {beta}2-AR Signal Transduction... Implications of {beta}2-AR... Summary and Perspectives References

 
Abstract—Recent studies have added complexities to the conceptual framework of cardiac ß-adrenergic receptor (ß-AR) signal transduction. Whereas the classical linear G_s–adenylyl cyclase–cAMP–protein kinase A (PKA) signaling cascade has been corroborated for ß₁-AR stimulation, the ß₂-AR signaling pathway bifurcates at the very first postreceptor step, the G protein level. In addition to G_s, ß₂-AR couples to pertussis toxin–sensitive G_i proteins, G_i2 and G_i3. The coupling of ß₂-AR to G_i proteins mediates, to a large extent, the differential actions of the ß-AR subtypes on cardiac Ca²⁺ handling, contractility, cAMP accumulation, and PKA-mediated protein phosphorylation. The extent of G_i coupling in ventricular myocytes appears to be the basis of the substantial species-to-species diversity in ß₂-AR–mediated cardiac responses. There is an apparent dissociation of ß₂-AR–induced augmentations of the intracellular Ca²⁺ (Ca_i) transient and contractility from cAMP production and PKA-dependent cytoplasmic protein phosphorylation. This can be largely explained by G_i-dependent functional compartmentalization of the ß₂-AR–directed cAMP/PKA signaling to the sarcolemmal microdomain. This compartmentalization allows the common second messenger, cAMP, to perform selective functions during ß-AR subtype stimulation. Emerging evidence also points to distinctly different roles of these ß-AR subtypes in modulating noncontractile cellular processes. These recent findings not only reveal the diversity and specificity of ß-AR and G protein interactions but also provide new insights for understanding the differential regulation and functionality of ß-AR subtypes in healthy and diseased hearts.

Key Words: ß-adrenergic receptor subtype • G protein • cAMP compartmentalization • heart failure

	Overview: Myocardial ß-Adrenergic Receptors

Top Abstract Overview: Myocardial {beta}... Distinct {beta}-AR Subtype... {beta}2-AR Signal Transduction... Implications of {beta}2-AR... Summary and Perspectives References

 
Adrenergic receptor (AR) stimulation by catecholamines provides the most important regulatory mechanism for cardiovascular performance. The adrenergic receptors were classified as (for excitatory) and ß (for inhibitory) by Ahlquist¹ in 1948 on the basis of their functional behavior in blood vessels, ie, vasoconstriction versus vasodilation. Ahlquist’s classification was expanded by Lands et al,² who recognized that both - and ß-ARs could be further categorized into 2 distinct subtypes based on their relative potencies for the ligands available at that time. The cloning of a cDNA for the human ß₂-AR and subsequent studies indicate that the ß-ARs are members of the G protein–coupled receptor superfamily, which shares a common feature, the 7-transmembrane-spanning domains.^{3 4}

A dogma of cardiac ß-AR signal transduction is that the agonist-bound ß-AR selectively interacts with the stimulatory G protein (G_s), which activates adenylyl cyclase, catalyzing cAMP formation. Subsequently, activation of cAMP-dependent protein kinase A (PKA) leads to phosphorylation of regulatory proteins involved in cardiac excitation-contraction (EC) coupling and energy metabolism, including L-type Ca²⁺ channels, the sarcoplasmic reticulum (SR) membrane protein phospholamban (PLB), myofilament proteins, and glycogen phosphorylase kinase. PKA also phosphorylates and thereby activates an endogenous protein phosphatase inhibitor I, which further ensures the PKA-mediated protein phosphorylation by inhibiting protein phosphatases.^{5 6} In addition to these acute effects, chronic ß-AR stimulation affects multiple cellular functions, including gene transcription, cell growth, and death. After its activation, ß-AR signaling is modulated at both the receptor level and downstream of the cascade by the coordinated actions of at least 3 groups of enzymes: G protein–coupled receptor kinases (GRKs), which phosphorylate and thus desensitize the receptor; cyclic nucleotide phosphodiesterases (PDEs), which hydrolyze cAMP; and phosphatases, which dephosphorylate phosphoproteins.

Although several ß-AR subtypes have been cloned and pharmacologically characterized, those expressed in cardiomyocytes were initially thought to be exclusively the ß₁-AR subtype.² However, the traditional notion that only ß₁-AR modulates cardiac contractile function has been challenged by recent studies that provide compelling evidence that at least both ß₁-AR and ß₂-AR functionally coexist in cardiomyocytes of many mammalian species, including humans. Many investigators have struggled to understand whether the coexpression of ß-AR subtypes represents functional redundancy. An alternative, but equally appealing, concept is that these ß-AR subtypes mobilize identical signal transduction pathways but fulfill distinct physiological and pathophysiological roles. Another possibility is that ß-AR subtypes elicit distinct cardiac responses through different signaling pathways. Over the past decade, increasing evidence has demonstrated striking qualitative and quantitative differences in the functions and signaling mechanisms of the cardiac ß₁-AR and ß₂-AR subtypes. In the present review, we will highlight recent advances in cardiac ß-AR subtypes (particularly ß₂-AR signal transduction) that reveal a new level of diversity and specificity of cardiac ß-AR subtype stimulation and provide a conceptual framework for our understanding of the physiological and pathophysiological significance of the coexistence of receptor subtypes.

	Distinct ß-AR Subtype Actions in the Heart

Top Abstract Overview: Myocardial {beta}... Distinct {beta}-AR Subtype... {beta}2-AR Signal Transduction... Implications of {beta}2-AR... Summary and Perspectives References

 
Despite many similarities, ß₁-AR and ß₂-AR are genetically and pharmacologically distinct entities. The amino acid sequences of human ß₁-AR and ß₂-AR share only 71% identity in the 7-transmembrane-spanning domains and 54% identity overall.^{3 4} Thus, it is plausible that ß-AR subtypes could couple to distinct signal transduction pathways and elicit different cellular responses. In this section, we will examine evidence for qualitative and quantitative differences between ß₁-AR and ß₂-AR with respect to G protein coupling, cAMP handling, target protein phosphorylation, and modulation of cardiac EC coupling.

ß-AR Subtypes Differentially Regulate Ca²⁺ Handling and Contractility
Cardiac EC coupling is initiated by a Ca²⁺ influx through voltage-dependent sarcolemmal L-type Ca²⁺ channels during an action potential. This Ca²⁺ influx per se is insufficient to produce a contraction, but it triggers a large Ca²⁺ release from the SR via ryanodine receptors through a Ca²⁺-induced Ca²⁺ release mechanism.⁷ The resultant intracellular Ca²⁺ (Ca_i) transient activates contractile proteins, producing a contraction; Ca_i is subsequently removed from the cytoplasm by the SR Ca²⁺-ATPase (Ca²⁺ pump) and the sarcolemmal Na⁺-Ca²⁺ exchanger. ß-AR stimulation modulates virtually all of these important components of the cardiac EC coupling cascade and therefore plays a prominent role in the regulation of cardiac performance.

There are several striking physiological differences between ß₁-AR and ß₂-AR subtypes. In rat ventricular myocytes, whereas stimulation of both ß-AR subtypes increases L-type Ca²⁺ currents (I_Ca), Ca_i transients, and contraction amplitude (positive inotropic effect), only ß₁-adrenergic stimulation markedly accelerates the Ca_i transient decay and contractile relaxation (positive lusitropic or relaxant effect).⁸ The absence of ß₂-AR–mediated cardiac relaxation has been also observed in many other mammalian species (eg, cat and sheep),^{9 10} but human and canine hearts are exceptions.^{11 12 13 14} Since ß-AR–induced cardiac relaxation is mainly mediated by PKA-dependent phosphorylation of PLB, an SR membrane protein,^{15 16} the different relaxant effects of ß-AR subtypes may largely be attributable to their distinct effects on PLB phosphorylation (see below). Additionally, ß₁-AR but not ß₂-AR stimulation reduces Ca_i-myofilament interaction.⁸ The differential regulation of myofilament sensitivity to Ca²⁺ by ß-AR subtypes may be also related to the ß₁-AR–induced phosphorylation of myofilament proteins (see below), which inhibits the myofilament response to Ca²⁺. Thus, both an increased SR Ca²⁺ uptake and a decreased myofilament Ca²⁺ sensitivity contribute to the relaxant effect after stimulation of ß₁-AR but not ß₂-AR. Concomitant with the enhanced SR Ca²⁺ recycling, only ß₁-AR stimulation increases the resting cytosolic Ca²⁺ and the likelihood of spontaneous Ca²⁺ oscillations in several mammalian species.^{8 17 18} This observation suggests that ß₁-ARs may be more prone than ß₂-ARs to elicit Ca²⁺-dependent arrhythmias. These functional differences between ß₁-AR and ß₂-AR stimulation suggest that there may be substantial differences in their intracellular signal transduction pathways.

ß₂-AR–Stimulated Ca_i and Contractile Responses Can Be Dissociated From Global Increases in cAMP and PKA-Mediated Phosphorylation of Cytoplasmic Proteins
In rat ventricular myocyte preparations, the dose-response curve of total cAMP accumulation induced by ß₁-AR stimulation with norepinephrine (NE) overlaps that induced by ß₂-AR stimulation with zinterol.¹⁹ However, the maximal increase in the particulate cAMP induced by zinterol is 50% of that caused by ß₁-AR,¹⁹ suggesting differential compartmentalization of cAMP after ß-AR subtype stimulation. Surprisingly, the ß₂-AR–stimulated increases in the particulate and total cAMP levels are apparently dissociated from the positive inotropic effect or the increase in Ca_i transients in adult rat myocytes; in contrast, ß₁-AR–stimulated increase in cAMP in either fraction is closely correlated with the cardiac functional changes.¹⁹ A more striking example of this dissociation has been observed in canine cardiomyocytes, in which the ß₂-AR–mediated augmentation of the Ca_i transient or contraction occurs in the absence of a measurable elevation of cAMP production.^{13 14}

To elucidate ß-AR subtype signaling downstream from cAMP, the PKA activity in both soluble and particulate fractions and the phosphorylation state of major regulatory proteins involved in cardiac EC coupling or in energy metabolism have been systematically examined in canine hearts. Stimulation of ß₂-AR fails to increase PKA activity in either fraction.¹⁴ In both rat and canine ventricular myocytes, ß₂-AR activation has only a negligible effect on PLB phosphorylation,^{13 14 19} relative to that after ß₁-AR activation. These results obtained from single isolated cardiomyocytes have been recently validated in intact animals. Anesthetized dogs exhibited positive chronotropic, inotropic, and lusitropic effects during ß₂-AR stimulation, and these effects occur without a detectable increase in PKA activation or PKA-dependent phosphorylation of nonsarcolemmal target proteins, such as glycogen phosphorylase kinase in the cytoplasm, troponin I and C proteins in myofilaments, and PLB in the SR membrane.¹⁴ In contrast, ß₁-AR–stimulated cardiac effects are well correlated with an increase in phosphorylation of these key regulatory proteins.^{13 14 19 20} Thus, the lack of PKA-mediated protein phosphorylation during ß₂-AR stimulation in rat and dog hearts clearly indicates that, unlike ß₁-AR, ß₂-AR does not transmit its signal to cytoplasmic regulatory proteins, at least in these species. The reason is unclear for the PLB and troponin I phosphorylation-independent lusitropic effect of ß₂-AR stimulation in canine myocytes.

Localized cAMP Signaling During Cardiac ß₂-AR Stimulation
The aforementioned observations demonstrate that ß₂-AR signaling modulates I_Ca but cannot phosphorylate regulatory proteins remote from the cell surface membrane, suggesting that ß₂-AR signaling is tightly localized near the subsarcolemmal microdomain, in the vicinity of L-type Ca²⁺ channels (Figure). More direct evidence supporting localized ß₂-AR signaling has emerged from on-cell patch-clamp single L-type Ca²⁺ channel recordings. Although the effect of ß₁-AR stimulation is rather diffusive, the effect of ß₂-AR stimulation is extremely localized: the L-type Ca²⁺ channel responds only to local (agonist included in pipette solution) but not remote (agonist added in bathing solution) ß₂-AR stimulation.²¹ These results are in general agreement with the observation that in frog cardiomyocytes, in which the ß₂-AR subtype predominates,²² a local ß-AR stimulation by isoproterenol applied to one end of the cell has little stimulatory effect on remote L-type Ca²⁺ channels.²³

View larger version (35K): [in this window] [in a new window]   Figure 1. Dual coupling of cardiac ß2-AR to Gs and Gi proteins. The ß2-AR–coupled Gi activation functionally localizes the Gs-mediated adenylyl cyclase (AC)–cAMP/PKA signaling to the subsarcolemmal microdomain, perhaps by stimulating PDE or protein phosphatases (PP). In contrast, ß1-AR couples exclusively to Gs protein.

These results, particularly those in canine hearts, initially evoked doubts as to whether ß₂-AR cardiac response is mediated by a cAMP-dependent signaling pathway.^{8 13 14 19} It has been proposed that the cardiac effects of ß-AR (subtype not specified) might be, in part, mediated by a direct interaction between G_s subunits and L-type Ca²⁺ channels.^{24 25} However, accumulating evidence indicates that the effect of ß-AR stimulation on cardiac I_Ca is mediated exclusively by a cAMP-dependent mechanism.^{14 26 27 28} To delineate a role of cAMP-dependent PKA activation in ß-AR subtype signaling, specific PKA inhibitors, including Rp-cAMP, H-89, and a peptide PKA inhibitor (PKI), have been used. Most studies, except one in adult rat myocytes,²⁹ have demonstrated that PKA inhibitors (Rp-cAMP and H-89) not only block the effect of ß₁-AR stimulation but also completely reverse the effects of ß₂-AR.^{14 27 28} Similarly, in human and frog cardiac myocytes, the ß₂-AR–induced augmentation of I_Ca is totally prevented by PKI.³⁰ Taken together, several lines of evidence strongly support the idea that cAMP-dependent PKA activation is obligatory for ß₂-AR–mediated cardiac responses, but this ß₂-AR–stimulated cAMP/PKA signaling in some species is highly localized to the surface membrane and cannot transmit to nonsarcolemmal proteins (Figure).

Dual Coupling of ß₂-AR to G_s and G_i Proteins
In many biological systems, G_s and G_i proteins engage in cross talk with each other. This cross talk is usually mediated through different receptor families. For example, activation of muscarinic or adenosine receptors, prototypic G_i-coupled receptors, markedly antagonizes the positive inotropic effect of ß-ARs. Interestingly, early work in lipid vesicles had demonstrated a physical potential for a single receptor to couple promiscuously to more than one class of G proteins. ß-AR, for instance, couples to both G_s and G_i proteins.³¹ Using a photoaffinity labeling technique, recent studies have demonstrated such promiscuous G protein coupling of ß₂-AR in intact cardiomyocytes, as manifested by a ß₂-AR–stimulated incorporation of a photoreactive GTP analogue, [³²P]GTP-azidoanilide, into subunits of G_i2 and G_i3 in addition to G_s.²⁸ The maximal effect of ß₂-AR stimulation on G_i proteins is comparable to that of carbachol, a muscarinic receptor agonist.²⁸ Pertussis toxin (PTX) pretreatment or the ß₂-AR antagonist (ICI 118,551) prevents the ß₂-AR–mediated G_i activation. Because ß₁-AR stimulation is not able to increase G_i activity, the coupling to G_i is specific for ß₂-AR subtype.²⁸ Thus, ß₂-AR signaling exemplifies a unique mode of receptor–G protein interaction; ie, a given receptor simultaneously activates more than one class of G proteins routing to functionally opposing pathways. Furthermore, ß₁-AR and ß₂-AR exhibit subtype-selective coupling to G_s.^{32 33} A more recent in vitro study has revealed that ß₂-AR couples to different split variants of G_s and that the ß₂-AR coupled to the long splice variant displays ligand-independent constitutive activity.³⁴

Mechanisms underlying the differential coupling of ß-AR subtypes to G proteins are not well understood. At the molecular level, studies on chimeric or mutated G protein–coupled receptors (including the major subtypes of adrenergic receptors) have shown that the third cytoplasmic loop that connects transmembrane domains V and VI of these receptors is an important determinant for G protein coupling.^{35 36 37} For example, replacement of the cytoplasmic loop of muscarinic receptor with that of ß₂-AR can induce G_s activation in response to muscarinic agonists.³⁷ It has also been shown that a proline-rich region of the third intracellular loop determines the different G_s coupling and sequestration of ß₁-AR versus ß₂-AR.³³ Thus, the differences between ß₁-AR and ß₂-AR in G protein coupling could be eventually ascribed to some critical differences in the sequences of the cytoplasmic loop of the receptors. Recent evidence also suggests a potential role of posttranslation receptor modification in the receptor/G protein coupling. In HEK293 cells, PKA-mediated phosphorylation of ß₂-AR switches the receptor coupling preference from G_s to G_i.³⁸ At the cellular level, it has been suggested that ß-AR subtypes are located in 2 distinct cellular fractions after agonist stimulation: ß₁-AR in caveolae and ß₂-AR in coated pits.^{39 40} The difference in the subcellular distribution of ß-AR subtypes may also contribute to their distinct G protein coupling and differences in signaling. In other words, ß₂-ARs but not ß₁-ARs might be geometrically colocalized with the G_i proteins.

Involvement of ß₂-AR/G_i Coupling in Local Control of ß₂-AR–Stimulated cAMP Signaling
Functional localization of cAMP/PKA signaling could be ascribed to compartmentalization of cAMP or PKA per se (because of a localized activation of adenylyl cyclase or PDE)^{23 41} or to specific anchoring proteins of PKA.^{42 43} A close spatial association of L-type Ca²⁺ channels with adenylyl cyclase and PKA^{42 44 45} would provide a structural basis for the ß₂-AR–mediated cAMP-dependent local regulation of the channel. Nevertheless, in view of the fact that both cAMP and active PKA catalytic subunits are readily diffusible, additional constrictive mechanisms must be involved in the local control of the ß₂-AR cAMP/PKA signaling. In principle, this local control could also arise from counter–signal transduction pathways that locally negate the cAMP/PKA signaling.

Involvement of ß₂-AR–coupled G_i signaling in the compartmentalization of the G_s-mediated cAMP/PKA signaling has been investigated by using PTX to inhibit G_i functions. In rat ventricular myocytes, PTX treatment, which has no significant effect on baseline parameters, specifically potentiates the ß₂-AR–mediated positive inotropic effect.^{46 47} More remarkably, PTX treatment permits ß₂-AR stimulation to induce a robust dose-dependent increase in PLB phosphorylation,⁴⁸ accompanied by a marked relaxant effect.^{46 48} Thus, inhibition of G_i proteins by PTX causes ß₂-AR signaling to closely resemble that of ß₁-AR. In contrast, the ß₁-AR–mediated effects on cardiac EC coupling in rat ventricular myocytes are insensitive to PTX pretreatment,^{46 48} consistent with the inability of ß₁-AR to activate G_i proteins.²⁸ These studies indicate that at least in rat cardiomyocytes, ß₂-AR/G_i coupling underlies the functional compartmentalization of the ß₂-AR/G_s–directed cAMP/PKA signaling, which may largely account for the qualitative and quantitative differences between ß₁-AR– and ß₂-AR–mediated cardiac actions.

It has been noted that in rat ventricular myocytes, PTX treatment has no significant effect on the ß₂-AR–mediated global cAMP accumulation²⁷ or PKA activation.⁴⁸ The simplest explanation for these observations is that the cross talk of ß₂-AR–coupled G_i and G_s signaling occurs downstream from PKA rather than at the G protein or adenylyl cyclase level (Figure). In this regard, some evidence suggests that typical G_i-coupled receptors, such as the muscarinic receptor M₂ or adenosine receptor A₁, counteract the effect of PKA, in part, via activation of protein phosphatases.^{49 50} The role of protein phosphatases in ß₂-AR/G_i signaling has been recently suggested.⁴⁸ Alternatively, other evidence indicates that PDE is involved in the compartmentalization of ß-AR–mediated cAMP signaling in canine⁴¹ and frog²³ cardiac myocytes. Whether ß₂-AR/G_i coupling activates protein phosphatases, PDE, or other unknown second messengers to functionally compartmentalize the ß₂-AR/G_s–directed cAMP/PKA signaling awaits further study (Figure).

Possible Role of pH_i in Mediating the ß₂-AR Positive Inotropic Response
Recently, a G protein–independent mechanism underlying a ß₂-AR–mediated cellular response has been demonstrated.⁵¹ Specifically, ß-AR agonists can induce a direct physical association of Na⁺-H⁺ exchange (NHE) regulatory factor (NHERF), an inhibitor of Na⁺-H⁺ exchanger type 3 (NHE3), to the C-terminus of ß₂-AR, relieving the inhibitory effect of NHERF on NHE3. Thus, ß₂-AR stimulation can exert opposing effects on NHE3 activity: a stimulatory effect induced by the direct association of ß₂-AR with NHERF and an inhibitory effect mediated by PKA-dependent phosphorylation of NHERF, thereby activating NHERF. The relevance of this phenomenon to ß₂-AR signaling in cardiomyocytes, however, has not yet been explored. It has been proposed that ß₂-AR activation in adult rat ventricular myocytes increases pH_i, in a PKA-independent and Na⁺-H⁺-independent manner, resulting in an enhanced contractile response.²⁹ In contrast, most studies have found that the ß₂-AR–mediated positive inotropic effect is closely related to a proportional increase in Ca_i transient or I_Ca^{8 13 14 19 27 28} and can be completely reversed by specific PKA inhibitors.^{14 27 28 48} Quantitative studies are required to determine the relative contributions of changes of pH_i and Ca_i to the ß₂-AR contractile response.

Diversity of Cardiac ß₂-AR Signaling Among Mammalian Species
In addition to the differences in the behavior of ß-AR subtypes within species, there is also a great diversity in ß₂-AR–mediated cardiac responses among species. At one extreme, in murine and guinea pig cardiomyocytes, ß₂-AR stimulation normally elicits no significant contractile response.^{28 52} In mouse cardiomyocytes, PTX treatment unmask a de novo ß₂-AR–mediated contractile response.²⁸ At the other extreme, in the chronically failing human atrium and ventricle, ß₂-AR stimulation induces positive inotropic and lusitropic effects and phosphorylation of regulatory proteins.^{11 12} Between these extremes, in isolated rat and canine ventricular myocytes, ß₂-AR–mediated I_Ca, Ca_i transient, and contractile responses are present but can be further enhanced by PTX treatment.^{46 48} It is possible that this species-dependent diversity of cardiac ß₂-AR signaling may be largely accounted for by differences in the extent of ß₂-AR/G_i coupling among species. For example, the ß₂-AR/G_i coupling would be expected to be extremely robust in mouse heart, but it might be less efficient in human hearts compared with mouse and rat hearts. It should be cautioned that most human studies have been conducted in preparations from chronically failing hearts, and to date, no data are available on the effect of PTX on ß₂-AR responsiveness in normal human myocardial preparations. Thus, it is not clear whether these pathophysiological conditions, such as chronic heart failure, influence the ß₂-AR coupling to G_s versus to G_i proteins.

It is noteworthy that avian species appear to use markedly different signal transduction pathways. For example, in embryonic chick ventricular myocytes, ß₂-AR stimulation by zinterol increases the Ca²⁺ transient and contractility by increasing arachidonic acid, which is negatively regulated by cAMP/PKA signaling pathway.⁵³

Developmental Changes in Cardiac ß-AR Subtype Signaling
In contrast to adult rat myocytes, ß₂-AR stimulation by zinterol in neonatal rat ventricular myocytes leads to increased intracellular cAMP accumulation and enhanced phosphorylation of PLB and troponin I, associated with an increase in the amplitude and an acceleration of the kinetics of the contraction and Ca_i transient.⁵⁴ All of these responses are similar to those elicited by ß₁-AR stimulation in neonatal rat myocytes. Interestingly, the dose-response curve of contraction in response to ß₂-AR stimulation by zinterol is shifted 2 orders of magnitude leftward in neonatal myocytes compared with adult myocytes. Thus, ß₂-ARs may play a more important role in mediating the response to catecholamines in the noninnervated neonatal (or transplanted) heart than in the innervated adult heart. This developmental change in cardiac ß₂-AR responsiveness is not due to a higher proportion of ß₂-ARs in the neonatal heart, because the ratio of ß₂-ARs to ß₁-ARs is similar in both preparations.⁵⁴ It is noteworthy that the contractile dose-response relation to the ß₂-AR agonist zinterol in neonatal rat myocytes⁵⁴ is similar to that in PTX-treated adult rat myocytes.⁴⁶ Thus, it might be speculated that the ß₂-AR coupling to G_i proteins might be acquired or reinforced during development, and this could explain the greater sensitivity of neonatal ß₂-AR stimulation in the absence of PTX. In other words, in neonatal rat myocytes, the ß₂-AR/G_i coupling is lacking or insufficient to negate the G_s-mediated relaxant effect and phosphorylation of regulatory proteins.

	ß2-AR Signal Transduction in Genetically Manipulated Murine Models

Top Abstract Overview: Myocardial {beta}... Distinct {beta}-AR Subtype... {beta}2-AR Signal Transduction... Implications of {beta}2-AR... Summary and Perspectives References

 
Rapid advances in mouse genetics have provide powerful tools to unravel the molecular secrets that govern cardiovascular structure and function in health and disease. Several transgenic mouse models have been developed to manipulate ß-AR signal transduction pathways.^{55 56 57 58} In addition, ß₁-AR or ß₂-AR and ß₁-/ß₂-AR double-knockout mice have recently been generated.^{59 60 61} In this section, we will briefly discuss some principles and lessons learned from these transgenic and gene-targeted mice. Discussion involving genetic manipulation and ß-AR signaling in the setting of cardiac hypertrophy and heart failure will be deferred to "Implications of ß₂-AR Signaling in Heart Failure."

Spontaneous ß₂-AR Activation
In TG4 transgenic mice, cardiac-specific overexpression of ß₂-AR by 200-fold leads to an agonist-independent enhancement in both the baseline adenylyl cyclase activity and myocardial contractility in vivo⁵⁵ and in isolated atria⁵⁷ or single cardiomyocytes.²⁸ This transgenic model opens a new avenue in the study of ligand-free ß-AR signaling. According to the prevailing 2-state model, G protein–coupled receptors, like ß-ARs, exist in an equilibrium between 2 functionally and conformationally distinct states: an inactive conformation (R) and an active conformation capable of activating G proteins (R*).^{55 57 62} In the absence of a receptor ligand, the receptor can undergo a spontaneous transition to the activated state; the equilibrium between R and R* sets the level of basal receptor activation. Thus, an overexpression of a given receptor would be expected to proportionally increase the number of R* state receptors. Receptor agonists have a higher affinity for R*, thereby shifting the equilibrium to the active conformation R*. Neutral antagonists bind with equal affinity to R and R*, and therefore inhibit receptor signaling without altering the equilibrium between R and R*. A third class of receptor ligands known as inverse agonists preferentially binds to R, driving the equilibrium toward the inactive conformation R. As shown in TG4 mice, the enhanced basal cardiac adenylyl cyclase activity and contraction are reversed by a ß₂-AR inverse agonist, ICI 118,551, both in vivo and in vitro.^{28 55 57} At the moment, it is unclear whether ß₁-AR and ß₂-AR have similar abilities to undergo spontaneous activation.

Spontaneous and Agonist-Induced Active ß₂-ARs Exhibit Different Signaling
Although a 2-state model for the adrenergic receptor is sufficient to explain many aspects of ß₂-AR activation, multiple active functional states of the receptor have been demonstrated.^{63 64 65} This idea is reinforced by several important differences between spontaneously activated ß₂-ARs and agonist-stimulated ß₂-ARs in TG4 cardiomyocytes. First, whereas spontaneously active ß₂-ARs significantly increase the baseline contractility of the TG4 heart, ß₂-AR agonists, at maximal concentrations, are unable to further increase contraction amplitude, even though the contractility is not yet saturated. Second, whereas ß₂-AR agonists induce a marked increase in I_Ca, ligand-independent constitutive ß₂-AR activation increases cardiac contractility but cannot modulate I_Ca.⁶⁶ Finally, spontaneously activated ß₂-ARs and agonist-stimulated ß₂-ARs may differentially couple to G_i proteins, because PTX robustly enhances the ß₂-AR agonist–mediated contractile response but only slightly enhances the effect of spontaneous ß₂-AR signaling on basal contractility in TG4 heart cells.²⁸ These occurrences suggest that spontaneously active ß₂-ARs and agonist-activated ß₂-ARs may represent functionally distinct conformational states of the receptor.

Compensatory Changes in Genetically Manipulated Animal Models
A peculiar feature of TG4 mice is that ß₂-AR overexpression causes a marked reduction in PLB expression, which contributes to the accelerated basal cardiac relaxation.⁶⁷ Additionally, in transgenic mice overexpressing G_s, there is a significant upregulation of ß-adrenergic receptor kinase (ßARK).⁶⁸ In fact, in many transgenic models, a specific or even a global remodeling process such as hypertrophy is accompanied by the upregulation or downregulation of a gene or set of genes^{69 70} (for a review, see Reference 71⁷¹ ). Although these compensatory changes might be beneficial for the animal’s survival, they introduce complications in understanding their phenotypes. Thus, caution should be exercised when drawing a direct mechanistic link between genetic manipulations and phenotypes.

	Implications of ß2-AR Signaling in Heart Failure

Top Abstract Overview: Myocardial {beta}... Distinct {beta}-AR Subtype... {beta}2-AR Signal Transduction... Implications of {beta}2-AR... Summary and Perspectives References

 
A large body of evidence has demonstrated that the cardiac response to ß-AR stimulation decreases in chronically failing hearts in human and animal models, and that there is a positive correlation between increased plasma catecholamine levels and the degree of the diminution of the ß-AR response.^{72 73 74 75} The demonstration of promiscuous ß₂-AR coupling to G_s and G_i also provides new insights into the pathogenesis of heart failure.

Distinct Phenotypes Induced by Chronic ß₁-AR Versus ß₂-AR Stimulation
The ß-AR subtypes have markedly different chronic effects on cardiac hypertrophy, as manifested by the distinct phenotypes of transgenic mice overexpressing cardiac ß₁-AR versus ß₂-AR. For example, vast overexpression of cardiac ß₂-AR by 200-fold does not induce detectable cellular hypertrophy or heart failure, at least in the short term.^{28 55 57} In contrast, low level (5- to 15-fold) overexpression of ß₁-AR results in cardiac hypertrophy and heart failure.⁵⁸ This phenotype is similar to that obtained by transgenic overexpression of cardiac G_s in mice⁷⁶ or by chronic ß-AR stimulation by agonist infusion.^{77 78} Furthermore, heart-specific overexpression of ß₂-AR at 30-fold not only rescues ventricular function but also reverses cardiac hypertrophy induced by transgenic overexpression of G_q.⁷⁹ Emerging evidence also indicates that these ß-AR subtypes even have opposing effects on apoptosis in cultured rat cardiomyocytes: ß₁-AR stimulation induces apoptosis,^{80 81} whereas ß₂-AR stimulation inhibits apoptosis.^{81 82} These studies shed new light on whether long-term ß-AR stimulation is beneficial. Answering this question may require discriminating ß-AR subtypes, because ß₁-AR and ß₂-AR have distinct, even opposite, chronic effects.

Differential Regulation of ß₁-AR Versus ß₂-AR in Failing Hearts
Except for mitral valve disorder–induced heart failure,⁸³ most studies involving end-stage human heart failure^{73 74 75 84} and some heart failure animal models^{72 85} have shown a selective decrease in ß₁-AR number with little or no loss of ß₂-AR. The selective reduction in ß₁-AR density may be attributed to elevated plasma levels of NE, which has a higher affinity for ß₁-AR.² In the line of the distinct phenotypes of transgenic overexpression of ß₁-AR versus ß₂-AR, the selective downregulation of ß₁-AR may reflect a protective mechanism in the failing heart. However, the ß₂-AR–mediated cardiac response, similar to that of ß₁-AR, is also significantly diminished.^{73 74 75 84 85} Next, we will discuss possible role of ß₂-AR/G_i coupling in the loss of ß₂-AR contractile response in heart failure.

Upregulation of G_i Proteins in Heart Failure
Studies in rat and guinea pig have shown that chronic infusion of catecholamines increases the expression of G_i.^{86 87} In transgenic mice, in which the human ß₂-AR is overexpressed, the G_i protein abundance is also significantly enhanced.²⁸ These results suggest that chronic ß-AR stimulation elevates G_i expression. Increasing evidence has demonstrated that heart failure is associated with elevated plasma catecholamine levels, which could result in an increase in G_i protein abundance or function. Indeed, in chronic heart failure in both humans^{88 89} and animal models,⁷² marked increases in G_i mRNA levels, PTX-induced ribosylation, and G_i abundance have been reported. Because the coupling of ß₂-AR to G_i proteins negatively regulates the G_s-mediated contractile response in the heart of many mammalian species,^{27 28 46 47 48} the enhanced G_i signaling might serve as a mechanism underlying the diminution of the ß₂-AR–stimulated positive inotropic effect. In human chronic heart failure, some evidence suggests that G_i proteins may be also involved in the diminution of ß₁-AR contractile response.⁹⁰

G Protein–Coupled Receptor Kinases in Failing Hearts
Agonist-dependent desensitization can be initiated by phosphorylation of activated receptors by members of the GRK family.⁹¹ ßARK1 is a prototypic GRK that has been shown to phosphorylate activated ß₁-AR and ß₂-AR subtypes in vitro.^{92 93} Phosphorylated receptors become binding substrates for a class of inhibitor proteins, ß-arrestins, which inhibit further G protein coupling.⁹⁴ Recently, it has been demonstrated that overexpression of a second myocardial GRK, GRK5, in transgenic mice also leads to significant cardiac ß-AR uncoupling.⁹⁵ In chronic human heart failure, the levels and enzymatic activity of ßARK1 are significantly elevated.⁹⁶ In heart failure animal models, ßARK1 activity is also correlated with ß-AR responsiveness.⁹⁷ Transgenic mice with myocardial overexpression of ßARK1 (3- to 5-fold) have a blunted contractile response to ß-AR stimulation by isoproterenol^{56 98} or NE.⁹⁹ More strikingly, a genetic model of murine heart failure (MLP-/-) can be largely reversed by an overexpression of ßARK1 inhibitor.¹⁰⁰ Taken together, chronic heart failure is associated with a marked increase in G_i proteins, a selective downregulation of ß₁-AR (higher ß₂/ß₁), and an increased expression and activity of GRK2 (ßARK1). The exaggerated ß₂-AR/G_i signaling and the enhanced ßARK1 activity may contribute to the heart failure–associated dysfunction of ß-AR stimulation and play a critical role in the pathogenesis of heart failure.

	Summary and Perspectives

Top Abstract Overview: Myocardial {beta}... Distinct {beta}-AR Subtype... {beta}2-AR Signal Transduction... Implications of {beta}2-AR... Summary and Perspectives References

 
In summary, recent studies have demonstrated that the cardiac ß₁-AR and ß₂-AR are markedly different regarding to G protein coupling, cAMP handling, target protein phosphorylation, and modulation of cardiac EC coupling. Many of these differences can be explained by the additional coupling of ß₂-AR to G_i proteins, which, in some species and developmental stages at least, functionally localizes the ß₂-AR/G_s–mediated cAMP/PKA signaling to the subsarcolemmal microdomain. This ß₂-AR/G_i pathway may also contribute to the distinct phenotypes of overexpression of cardiac ß₂-ARs versus ß₁-ARs in transgenic mouse models. Thus, it is necessary and important to distinguish ß₂-ARs from ß₁-ARs with regard to their physiological and pathophysiological roles.

Many important questions remain to be answered. Further studies are required to determine the molecular, structural, and microarchitectural bases underlying the differential G protein coupling of ß₂-AR versus ß₁-AR. Information on downstream signaling of ß₂-AR–coupled G_i proteins only begins to emerge. In addition, studies of the chronic noncontractile effects of cardiac ß-AR subtype stimulation, eg, on cardiac cell growth and death, will broaden and deepen our understanding of the differential regulation and functionality of ß-AR subtypes in health and disease. Finally, the possible role of ß₂-AR/G_i coupling in the pathogenesis of chronic heart failure merits future investigation.

Received March 2, 1999; accepted September 15, 1999.

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Top Abstract Overview: Myocardial {beta}... Distinct {beta}-AR Subtype... {beta}2-AR Signal Transduction... Implications of {beta}2-AR... Summary and Perspectives References

 
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