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(Circulation Research. 1999;85:1101.)
© 1999 American Heart Association, Inc.

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The Molecular Basis for Distinct ß-Adrenergic Receptor Subtype Actions in Cardiomyocytes

Susan F. Steinberg

From the Departments of Pharmacology and Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.

Correspondence to Susan F. Steinberg, MD, Associate Professor of Pharmacology and Medicine, Department of Pharmacology, College of Physicians and Surgeons, Columbia University, 630 West 168th St, New York, NY 10032. E-mail sfs1{at}columbia.edu

Key Words: ß-adrenergic receptor subtype • cardiomyocyte • cAMP • contractility

	Introduction

Top Introduction The {beta}-AR Complex: A... Distinct Signaling Pathways... Conclusions and Questions for... References

 
Catecholamines exert physiologically important effects on the electrical properties and mechanical performance of the heart through the activation of adrenergic receptors. It has been 50 years since Ahlquist¹ first postulated that the excitatory and inhibitory pressor responses to catecholamines must be mediated by distinct adrenergic receptors (ARs), then designated (for excitatory) and ß (for inhibitory). Ahlquist’s classification was expanded further by Lands et al,² who recognized that both - and ß-ARs could be conveniently categorized into 2 distinct subtypes on the basis of their relative potencies for ligands available at that time. In the ensuing years, the predominant AR expressed by cardiomyocytes was shown to conform to the ß₁-AR subtype. Our understanding of the molecular basis for sympathetic modulation was advanced further by the observations that under normal physiological conditions catecholamines induce positive inotropic, chronotropic, and lusitropic (relaxant) responses in the heart through a ß₁-AR–activated pathway, which involves the stimulatory GTP regulatory protein (G_s), activation of adenylyl cyclase (AC), accumulation of cAMP, stimulation of cAMP-dependent protein kinase A (PKA), and phosphorylation of key target proteins (including the L-type calcium channel [I_Ca,L], phospholamban [PLB], and troponin I [TNI]). Potential contributions of other AR subtypes to the mechanism(s) of catecholamine action in the heart were largely ignored in early studies. However, the traditional notion that only ß₁-ARs support cardiac contractile function has been challenged by recent research demonstrating that cardiac myocytes also express ß₂-ARs that link to important changes in cardiac contractile function. Although these ß₂-AR–dependent signals may represent only a relatively minor component of catecholamine responsiveness under normal physiological conditions, ß₂-ARs assume increased importance as a mechanism for inotropic support in the failing or aged heart, where there is a selective downregulation of ß₁-ARs.^{3 4 5 6} The evidence that ß₂-ARs are upregulated in denervated, transplanted human hearts,^{7 8} recent clinical trials showing that nonselective ß-blockers reduce sudden cardiac death in the post–myocardial infarction period, whereas ß₁-AR–selective blockers do not,⁹ and the identification of a polymorphism of the ß₂-AR that modifies the prognosis of patients with congestive heart failure¹⁰ have contributed to current, more widespread, acceptance of the notion that ß₂-ARs have been underestimated as important modulators of clinical outcome in the setting of myocardial dysfunction. Thus, the focus of recent research has been to determine whether the coexpression of structurally homologous stimulatory ß-AR subtypes represents functional redundancy or, rather, a mechanism to critically regulate receptor responsiveness through a previously unappreciated level of heterogeneity in postreceptor components of the receptor complex (as schematized in Figure 1). An alternative, but equally compelling, hypothesis is that stimulatory ß-AR subtypes mobilize identical signal transduction pathways but fulfill distinct physiological roles because of their spatially or developmentally specific patterns of expression. This review summarizes recent research that lends credence to each of these concepts and has served to reshape our understanding of the molecular and cellular mechanisms that underlie postjunctional ß-AR control of cardiomyocyte function.

View larger version (31K): [in this window] [in a new window]   Figure 1. Schematic of pathways activated by ß-adrenergic receptor subtypes. With the exception of the data on signaling by the ß2-AR C-terminal tail, all pathways included in the schematic represent responses that have been identified in cardiomyocytes. Other mechanisms also linked to ß-ARs in mammalian cardiomyocytes include a bicarbonate-dependent pH-regulatory mechanism that leads to intracellular alkalinization (for the ß2-AR) and the ERK subfamily of mitogen-activated protein kinases (ß-AR subtype not characterized). These are not included, as their G protein requirements are as yet unknown. Broken line denotes a molecular interaction.

	The ß-AR Complex: A Structural Basis for Functional Diversity

Top Introduction The {beta}-AR Complex: A... Distinct Signaling Pathways... Conclusions and Questions for... References

 
ß-Adrenergic Receptors
Although ß₁-ARs predominate in mammalian ventricular cardiomyocytes (ranging from 80% in various rat, canine, and feline cardiac preparations^{11 12 13 14} to 60% in baboon ventricular myocytes¹⁵ ), our understanding of the structural basis for ligand-dependent receptor activation derives in large part from studies of the ß₂-AR (the first G protein–coupled receptor to be cloned). The primary amino acid sequence of the ß₂-AR reveals 7 hydrophobic amino acid segments that are sufficiently long (20 to 28 amino acids) to span the lipid bilayer. These have been postulated to exist as -helical transmembrane-spanning domains (TMDs) that form a pocket or receptacle for receptor ligands. According to the prevailing model, a network of intramolecular interactions hold the TMDs of the receptor in a ring- or barrel-shape alignment that allows for multiple contact points between the side chains of amino acid residues in the TMDs and receptor ligands. For agonist ligands, the critical contact points have been mapped primarily to the third and fifth TMDs. Two serine residues (Ser204 and Ser207), which lie one -helical turn apart on the same side of the fifth TMD, form hydrogen bonds with the meta- and para-hydroxyl groups of the catecholamine ring. The cationic amino group at the other end of the classical catecholamine molecule electrostatically interacts with the carboxylate side chain of Asp113 in the third TMD.¹⁶ However, antagonist ligands (which tend to have more complex structures) also interact with an Asn312 in the seventh TMD.¹⁶ Relevant to this analysis, mutagenesis studies have provided evidence that ß-AR subtype specificity for agonist ligands is determined by amino acids in TMD IV, whereas subtype selectivity for antagonist ligands is defined by amino acids in TMDs VI and VII.¹⁷ ARs exist in an equilibrium between (at least) 2 structurally and functionally distinct states: an inactive conformation (generally designated R) and an active conformation capable of activating G proteins (designated R*). Agonist binding promotes the formation of the active state of the receptor; this involves a conformational rearrangement, with several lines of investigation identifying movements of TMDs III and VI as key events in this process.¹⁸ Studies in transgenic mice that overexpress ß₂-ARs in the heart support the notion that receptors can undergo a spontaneous transition to the activated state even in the absence of receptor ligand.¹⁹

The cytoplasmic surface of the receptor molecule, particularly the amino and carboxyl termini of the third intracellular loop, contain the most critical determinants of AR–G protein interactions. Persuasive evidence to support this conclusion includes the following: (1) relatively small synthetic peptides (15 amino acids) based on this sequence of the ß₂-AR can directly activate G_s in vitro,²⁰ (2) certain mutations targeted to a short stretch of the carboxyl terminal portion of the third intracellular loop result in a constitutively activated ß₂-AR,²¹ and (3) relatively small structural changes within this region of the ß₂-AR can shift its G protein– subunit specificity.^{22 23 24} Nevertheless, through deletional/site-directed mutagenesis techniques and the construction of chimeric receptors, regions in close apposition to the plasma membrane in the second cytoplasmic loops as well as the proximal portion of the C-terminal cytoplasmic tail also have been implicated in this process.^{22 25} Collectively, these studies suggest that the G protein activation "surface" of the receptor is not accessible for G protein interactions in the basal state, either because it is buried within the receptor/membrane structure or because the transmembrane-spanning helices that contribute domains to form the G protein activation "surface" are physically too widely separated.²⁶ Activation by agonist ligands leads to a conformational change in the receptor, which releases some tonic constraint and reveals (or assembles) the G protein activation surface, which is predicted to be distinct for different G protein subunits and serves to stabilize AR–G protein interactions. In this context, recent reports that individual ß-AR subtypes display distinct G protein specificities are noteworthy. Specifically, the available evidence suggests that ß₁-ARs are rather restricted in their interactions and only interact with G_s proteins.²⁷ In contrast, several studies have identified ß₂-AR coupling to both G_s and G_i proteins,^{22 23} including reports that PKA-dependent phosphorylation of the ß₂-AR switches its G protein specificity so as to attenuate its interaction with G_s (and AC) and enhance its interaction with G_i (leading to the release of ß subunits and activation of an extracellular signal–regulated kinase [ERK] cascade involving Src tyrosine kinases and Ras²³ ).

An inherent difference in the efficacy of ß₁- and ß₂-AR coupling to G_s and AC has been identified and mapped, at least in part, to the third intracellular loop.^{4 28 29} This region of the ß₁-AR is considerably longer than the corresponding region of the ß₂-AR because of the presence of an unusually proline-rich sequence that has been implicated as a negative modulator of ß-AR–G_s coupling (ie, its removal improves ß₁-AR–G_s coupling, whereas its insertion into the ß₂-AR impairs ß₂-AR–G_s coupling³⁰ ).

There also is evidence that ß₂-ARs can couple to the modulation of an effector response mechanism in a G protein–independent manner.³¹ Na⁺/H⁺ exchange regulatory factor (NHERF; a protein that is present in many tissues, but is expressed at especially high levels in the kidney) is a known inhibitor of the activity of the Na⁺/H⁺ exchanger type 3 (NHE3). NHERF was recently demonstrated to bind through its PDZ domain to the most C-terminal amino acids of the ß₂-AR; there is growing evidence that this may exemplify a more generalized G protein–independent signaling mechanism for certain G protein–coupled receptors.^{32 33} The interaction of NHERF with the ß₂-AR C-terminal cytoplasmic domain is agonist dependent (the antagonist-bound receptor conformation does not interact with NHERF) and functionally serves to release the inhibitory effects of NHERF on NHE3. These new results provide a scenario whereby ß₂-ARs can exert opposing effects on NHE3 activity. Through PKA-dependent phosphorylations of NHERF and NHE3 (in response to ß₂-AR agonists or other cAMP-elevating agents), these proteins are driven to associate with a resultant decrease in NHE3 activity. However, the direct interaction of ß₂-ARs with NHERF, which is presumed to sequester NHERF and/or to alter its conformation so that it no longer can interact with NHE3, increases NHE3 activity and tends to oppose this effect. Thus, these data may serve to reconcile previous anomalous observations on hormone-dependent regulation of Na⁺/H⁺ exchanger activity. The relevance of this mechanism to catecholamine-dependent inotropic responses in the heart (where a ß₂-AR–dependent alkalinization has been proposed as a mechanism to enhance contractile performance^{34 35} ) has not yet been explored.

G Proteins
G proteins are heterotrimers consisting of a guanine nucleotide–binding subunit and a tightly but noncovalently associated dimer of ß and subunits (see References 36 and 37^{36 37} for recent reviews). G proteins are classified according to the identity of their subunits, which are broadly grouped into 4 classes; G_s, G_i, G_q, and G_12/13. G_s and G_i figure most prominently in ß-AR subtype signaling, as they couple to the stimulation or inhibition of AC enzyme activity, respectively. Historically, G protein function was attributed entirely to the actions of the freed subunit. For G_i, this was accomplished largely with pertussis toxin (PTX), which catalyzes the ADP ribosylation of G_i, a covalent modification that blocks G_i-receptor interactions and thereby functionally inactivates signal transduction pathways mediated by _i subunits. However, more recent studies establish that G protein activation is a bifurcating process, with the liberated ß dimers also controlling various effector functions (either alone or in concert with the subunits). Additional properties that have been relegated to the ß dimer include directing the fidelity of G protein–coupled receptor-effector interactions and facilitating the agonist-dependent ß-AR phosphorylation/desensitization process by recruiting the G protein–coupled receptor kinase (GRK or ßARK) to the plasma membrane.^{38 39}

G proteins are critically regulated by both subunit dissociation (-ß) and guanine nucleotide exchange cycles. The latter is a highly regulated process; the lifetime of the active, GTP-bound, form of the subunit depends on the rate of the subunit GTPase, which is an intrinsic property of the subunit itself but also can be modified by the GTPase-activating protein activity of certain downstream effector proteins (such as phospholipase Cß⁴⁰ and AC⁴¹ ) and (for all subgroups of subunits except G_s) the newly described family of RGS (Regulators of G protein Signaling) proteins.⁴² Thus, for receptors that are capable of acting through multiple G proteins (such as the ß₂-AR), specificity in signaling may arise not only from the diverse pathways activated by distinct and ß subunits, but also from the actions of RGS proteins to modulate the guanine nucleotide exchange cycle kinetics of individual G subunits. Mammalian cells express >20 distinct RGS proteins; the biochemical/molecular properties of RGS4 have been most extensively characterized. RGS proteins accelerate the GTPase activity of subunits by binding to and stabilizing its transition state. However, the consequences of this action may not be confined to negative regulation of G subunit signaling, because the binding and sequestration of G subunits by RGS proteins also can impact positively on signaling by ß dimers.⁴³ Moreover, there is recent evidence that certain RGS proteins (particularly RGS4) interact with the combined receptor–G protein complex (not just the isolated G protein) and that this provides a mechanism for receptor-selective modulation of G protein signaling by RGS proteins.^{44 45} Cardiomyocytes isolated from rat heart are reported to express mRNAs for 10 RGS proteins, with evidence for regulation at the mRNA level during development and in certain cardiac hypertrophy and/or failure models.^{46 47} Insofar as large changes in mRNA are likely to be associated with coordinate changes in the cognate protein, this would be predicted to provide a potential mechanism for quantitatively distinct responses to agonist even in cells endowed with identical receptor/G protein composition (and could, at least in theory, be germane to ß₂-AR signaling in cardiomyocytes).

There currently are 5 known species of ß subunit and more than twice that number of subunits.^{38 48 49} ß subunits are the most conserved of the G protein subunits, whereas subunits are structurally quite divergent.^{50 51} Theoretically, an enormous number of different ß subunit combinations could be assembled, although there appear to be preferred associations between ß and subunits such that G proteins purified from different tissues differ with respect to their subunits.⁵² There is evidence that cardiomyocytes express at least 2 distinct species of ß (ß₁ and ß₂) and 4 different species of (_{3, 5}, ₇, and ₁₂) subunits at the protein level; one of these subunits (₃) is expressed in neonatal, but not adult, cardiomyocytes.^{48 53} One of the cardiac subunits (₇) recently was shown to play a specific role in the activation of AC by isoproterenol, but not by prostaglandin E₁.⁵⁴ These results emphasize the potential importance of subunits as specific facilitators (or restrictors) of receptor-effector coupling and suggest (the as-yet-unexplored notion) that changes in -subunit expression also may critically influence ß-AR responses in cardiomyocytes.

Adenylyl Cyclase
The mammalian AC gene family currently contains 9 members, with several detectable in cardiac tissue^{55 56} (reviewed in Reference 57⁵⁷ ). There is now persuasive evidence that the AC isoform composition of the cell membrane can critically influence cAMP accumulation; all membrane-bound forms of AC are activated by G_s, but they exhibit markedly different patterns of regulation by other cofactors such as ß subunits, calcium, and protein kinase C.^{55 57} Thus, it has been postulated that cells may vary in their capabilities to receive and integrate signals via the cAMP pathway as a result of differences in the ratio of individual AC isoforms.

Types V and VI AC are the predominant isoforms detected in cardiac preparations.^{58 59 60 61 62} These isoforms have been designated the cardiac subclass of AC on the basis of their structural homology (65% homology to each other and <40% homology to other isoforms of AC) and similar patterns of regulation by cofactors. Both isoforms are activated by the nonselective ß-AR agonist isoproterenol when overexpressed in HEK 293 cells. However, there is recent evidence that purinergic receptors couple to the stimulation of type V, but not type VI, AC.⁶³ The observation that purinergic receptors discriminate between cardiac AC isoforms suggests that individual AC isoforms may subserve specialized functions in cardiomyocytes. Moreover, this selectivity is not confined to the stimulatory pathway; purinergic receptor stimulation of AC (type V) is refractory to inhibitory modulation and contrasts with ß-AR activation of AC (types V and VI), which is attenuated by receptors that recruit G_i.⁶³ It is pertinent to note that normal cardiac ontogenic development is associated with a reciprocal change in steady-state levels of mRNAs encoding type V and type VI AC isoforms; the abundance of transcripts for type V AC increases and for type VI AC decreases with age.^{58 61} In the context of recent evidence that the abundance of the AC enzyme (a relatively sparse membrane protein) may set the limit on transmembrane ß-AR signaling,⁶⁴ it is intriguing to speculate that the abundance of the type V AC isoform calibrates the sensitivity of the purinergic receptor pathway (and fulfills a similar function for ß₂-ARs, where coupling to cAMP accumulation also is refractory to inhibitory modulation by muscarinic cholinergic agonists^{11 65} ).

	Distinct Signaling Pathways Mediating ß-AR Subtype Actions in Cardiomyocytes: Insights Gained From a Developmental Analysis

Top Introduction The {beta}-AR Complex: A... Distinct Signaling Pathways... Conclusions and Questions for... References

 
ß₁-ARs modulate cardiac contractility exclusively through a cAMP-dependent mechanism. However, the mechanism(s) underlying ß₂-AR actions in cardiac myocytes is less straightforward. Whereas ß₂-ARs also can link to the activation of AC (in fact, they inherently couple to the activation of AC more effectively than ß₁-ARs^{4 28 29} ), the relationship between ß₂-AR–dependent increases in cAMP accumulation and inotropic responses in the heart is tenuous. This has led to speculation that ß₂-ARs might couple to distinct compartments of cAMP and/or cAMP-independent inotropic mechanisms.^{3 4} Recent studies in neonatal and adult rat ventricular myocytes further bolster the notion that the signaling pathways mediating ß₁- and ß₂-AR–dependent modulation of contractile function must differ. These studies reveal important age-dependent differences in ß₂-AR coupling to more distal elements in the signaling cascade that lead to profound age-dependent differences in the mechanism for ß₂-AR–dependent modulation of contractile function. Insofar as the developmental paradigm identifies a framework to consider distinct pathways for ß₂-AR actions, the distinct characteristics of ß₂-AR responses in neonatal and adult rat ventricular myocytes are discussed separately in the sections that follow (and are schematized in Figure 2).

View larger version (12K): [in this window] [in a new window]   Figure 2. Distinct ß2-adrenergic receptor responses in neonatal and adult rat ventricular cardiomyocytes. Top, Effects of the ß2-AR agonist, zinterol, on cAMP accumulation in neonatal and adult rat ventricular myocytes. The significant, concentration-dependent increase in cAMP accumulation induced by zinterol in the newborn contrasts with the minimal increase in cAMP in the adult. Bottom, Representative tracings comparing the effect of ß2-AR activation on the amplitude and kinetics of cell contraction in neonatal and adult ventricular cardiomyocytes. ß2-AR activation was accomplished with zinterol, after a 5-minute pretreatment with the ß1-AR blocker CGP20712A (10-7 mol/L, to prevent any ß1-AR activation). The top tracing illustrates typical results obtained in a neonatal myocyte, in which a low concentration of zinterol increases the amplitude and accelerates the kinetics of the twitch. In neonatal myocytes, the motion of only 1 portion of the cell (rather than total cell length) is measured; for purposes of comparison, the position of a microsphere on the cell surface before electrical stimulation (diastole) is set to 0 and motion relative to the diastolic position before (solid line) and after (broken line) zinterol is reported. The bottom tracing illustrates a typical result obtained in adult cells, in which ß2-AR activation requires a 100-fold higher concentration of zinterol and is associated with an increase in the amplitude of the twitch, but a delay in its relaxation kinetics. In adult myocyte records, total cell length is reported. In each case, cell shortening is recorded as microns of motion and is represented as a downward deflection (adapted from Reference 11).

ß-AR Subtype Actions in Neonatal Cardiomyocytes
In neonatal rat ventricular myocytes, stimulation of ß₁-ARs leads to increased intracellular cAMP accumulation, enhanced phosphorylation of PLB and TNI, and an increase in the amplitude and an acceleration of the kinetics of the calcium and motion transients. All of these responses also are elicited by ß₂-AR stimulation with zinterol (Figure 2).^{11 65} Although it would be reasonable to assume that ß₁- and ß₂-ARs activate identical cAMP-dependent pathways in neonatal myocytes, recent studies provide intriguing evidence that this is not the case. These insights have come from attempts to understand the mechanisms that integrate input from the sympathetic and parasympathetic limbs of the autonomic nervous system. It is well known that muscarinic receptor agonists alone exert little or no direct effect on ventricular muscle contractility (sympathetic neuronal influences predominate). Nevertheless, they effectively antagonize the stimulatory response to ß-AR agonists in ventricular tissue. Early studies demonstrating that muscarinic receptors inhibit ß-AR–stimulated AC activity^{66 67 68} led to the notion that a reduction in cAMP constitutes the primary mechanism for muscarinic receptor-dependent actions in ventricular myocytes. However, the subsequent observations that muscarinic agonists only variably inhibit ß-AR–dependent cAMP accumulation, whereas the effects of muscarinic agonists to inhibit the enhanced contractility induced by ß-ARs are consistently demonstrated, suggests alternative inhibitory mechanisms.^{68 69 70 71} Recent studies provide novel evidence that muscarinic receptors inhibit individual ß-AR subtypes via distinct inhibitory pathways. As indicated in Figure 1, carbachol blocks ß₁-AR–dependent inotropic and lusitropic responses in neonatal rat ventricular myocytes by preventing the rise in cAMP. In contrast, carbachol acts through M₂ muscarinic receptors to block the ß₂-AR–dependent phosphorylation of PLB and TNI and the associated positive lusitropic response without interfering with cAMP accumulation or the positive inotropic response.⁶⁵ Although there is precedent to speculate that a G_i-dependent pathway, leading stimulation of a protein phosphatase and local inactivation of the cAMP signal at cytosolic and sarcoplasmic reticular PKA target proteins, provides a mechanism for the actions of carbachol,⁷² direct evidence is still lacking. Nevertheless, these studies indicate that at the level of cAMP accumulation, the pathway activated by the ß₂-AR is relatively refractory to inhibitory modulation by the parasympathetic limb of the autonomic nervous system. The observation that purinergic receptors specifically target to the activation of type V (and not of type IV or VI) AC and display a similar refractoriness to inhibitory modulation by adenosine⁶³ suggests a potential mechanism for the differential susceptibility of individual ß-AR subtypes to inhibitory modulation that requires further study.

ß-AR Subtype Actions in Adult Rat Ventricular Myocytes
Similar to the scenario in neonatal rat cardiomyocytes, ß₁-AR stimulation with isoproterenol induces a robust increase in cAMP accumulation that is associated with an increase in the amplitude and an acceleration of the kinetics of both the calcium transient and the twitch in adult rat ventricular myocytes. In contrast, only rather high concentrations of the ß₂-AR agonist zinterol (10^–5 mol/L) modulate contractile function in adult rat ventricular myocytes (Figure 2). Parenthetically, 2 laboratories have presented data to support the theoretical argument that 10^–5 mol/L zinterol (in the absence of a ß₁-AR blocker) acts as a mixed ß₁-/ß₂-AR agonist; ß₂-AR selectivity is achieved only if a ß₁-AR blocker (such as CGP 20712A) is included in the assay.^{11 73} In contrast, Xiao and Lakatta⁷⁴ maintain that the effects of high concentrations of zinterol (even without a ß₁-AR blocker) are attributable entirely to the minor population of ß₂-ARs in the preparation, and they present results to support this conclusion. Although the contention that 10^-5 mol/L zinterol alone (which would be predicted to lead to substantial ß₁-AR occupancy in cardiomyocytes with large ß₁-AR reserves) acts in the pure ß₂-AR mode remains perplexing and disputed by some investigators,⁷³ there is general agreement that ß₂-AR–dependent contractile responses are detected in adult rat cardiomyocytes only at 100-fold higher concentrations of zinterol than those required to elicit a response in neonatal rat cardiomyocytes (Figure 2). On the basis of this developmental difference in sensitivity to the cellular actions of ß₂-ARs, it has been speculated that ß₂-ARs (which would be activated by circulating epinephrine) may play a more important role in mediating the response to catecholamines in the noninnervated neonatal (or transplanted) than the innervated adult heart.¹¹ The mechanism underlying this age-dependent difference in the sensitivity of ß₂-ARs to agonist-induced activation has not yet been identified. It is not due to a higher proportion of ß₂-ARs in the neonatal heart, given that ß₂-receptors compose a similar minor proportion of the total ß-AR population in both preparations.¹¹

Activation of ß₂-ARs generally is reported to increase the amplitude of both the calcium transient and the twitch in adult cardiomyocytes^{11 74} (although no response to ß₂-AR stimulation was detected in a recent study in which the functional endpoints were restricted to calcium transients and L-type calcium current⁷³ ). Of note, ß₂-AR activation does not accelerate the relaxation kinetics of the calcium transient and twitch (ie, the response is quite distinct from the cAMP-dependent positive lusitropic response typically observed after ß₁-AR activation^{11 74} ). The literature on whether zinterol elevates intracellular cAMP in adult rat cardiomyocytes is conflicting. When agonist-dependent cAMP accumulation is measured in the presence of a phosphodiesterase inhibitor to prevent cAMP breakdown, a marked preferential stimulation of cAMP formation by ß₁-ARs, and not ß₂-ARs, is evident^{11 73} ; zinterol induces a 2-fold increase in intracellular cAMP accumulation over basal, which is very minor relative to the 15- to 20-fold increase over basal induced by isoproterenol (and potentially could arise from a minor population of contaminating noncardiomyocytes expressing ß₂-ARs in the preparation). In contrast, when cAMP breakdown is not inhibited by a phosphodiesterase inhibitor, ß-AR–dependent changes in intracellular cAMP content are reported to be very modest (only 50% to 80% above basal), and the responses to zinterol and isoproterenol are similar.⁷⁵ Under these conditions, the ß₂-AR–dependent increase in cAMP is reported to be most pronounced in the soluble compartment of the cell⁷⁴ where it is postulated to be dissociated from changes in calcium and contractile function (it has been argued that particulate, rather than soluble, cAMP and PKA play the dominant role in the phosphorylation of target substrates and the modulation of the inotropic state of the heart^{74 76 77 78} ).

The controversy is not limited to whether ß₂-ARs couple to cAMP accumulation in adult rat ventricular cardiomyocytes, but extends to the role of cAMP in the functional response to ß₂-AR stimulation. The evidence that ß₂-AR–dependent increases in the amplitude of the calcium transient and contraction are not accompanied by an acceleration in the kinetics of relaxation or any significant phosphorylation of PLB^{11 75} could suggest that ß₂-AR agonists modulate cardiac excitation-contraction coupling via a cAMP-independent mechanism. The observation that H7 (at concentrations predicted to inhibit PKA, protein kinase C, and cGMP-dependent protein kinase) blocks ß₁-AR–dependent positive inotropic and lusitropic responses but does not inhibit the mechanical response to ß₂-AR agonists is consistent with this formulation.³⁴ On the basis of further observations that for a given increase in intracellular calcium, there is a greater increase in twitch amplitude with ß₂-AR (relative to ß₁-AR) stimulation,⁷⁴ we have postulated that ß₂-ARs might activate a mechanism that leads to an increase in myofilament responsiveness to calcium. Indeed, recent studies demonstrate that the effect of ß₂-AR agonists to increase twitch amplitude is associated with a brisk intracellular alkalinization over a similar time course. This response is blocked by removal of bicarbonate from the extracellular buffer; it is not blocked by hexamethyleneamiloride and therefore is not likely to be mediated by the Na⁺/H⁺ exchanger.³⁴ These results argue that the ß₂-AR–dependent rise in pH_i leads to increased myofibrillar calcium sensitivity, which contributes to the mechanism for the ß₂-AR–dependent positive inotropic response.^{34 79} These data are consistent with an earlier report that ß-AR activation with isoproterenol induces a large stimulation of the Na⁺-HCO₃^– symport (and a moderate inhibition of the Na⁺-H⁺ antiport), which leads to an increase in net acid extrusion and tends to raise pH_i in guinea pig ventricular myocytes.³⁵ However, another cAMP-independent mechanism involving the activation of cytosolic phospholipase A₂ and the release of arachidonic acid has been implicated in ß₂-AR signaling in cultured embryonic chick ventricular cardiomyocytes (another cardiomyocyte model in which a ß₂-AR–dependent increase in intracellular calcium occurs in the absence of any detectable increase in AC activity and in a manner that resists the inhibitory actions of the cAMP antagonist Rp-cAMPS⁸⁰ ). Insofar as this pathway is reported to be mediated by a PTX-sensitive G protein, its relevance to adult rat ventricular cardiomyocytes (in which PTX is reported to potentiate, not block, ß₂-AR signaling⁸¹ ) is uncertain.

An alternative model also has been proposed to account for the ß₂-AR–dependent positive inotropic response in adult rat ventricular cardiomyocytes. In the context of the observation that the ß₂-AR–dependent increase in L-type calcium current is blocked by the inhibitory cAMP analogs Rp-cAMPS and Rp-CPT-cAMPS,⁸² Zhou et al⁸³ have argued that the functional response to ß₂-ARs is mediated by a cAMP pathway that is compartmentalized to the sarcolemma. These investigators have presented further evidence that PTX pretreatment potentiates the response to ß₂-AR (but not ß₁-AR) agonists (ie, that ß₂-ARs in adult ventricular myocytes couple to both G_s and a PTX-sensitive G_i protein that selectively dampens the cellular response to ß₂-AR agonists). The effects of PTX include a marked upward and leftward shift in the dose-response curve for the effects of zinterol on contraction amplitude⁸¹ and a de novo positive lusitropic response that is associated with PLB phosphorylation⁸⁴ (ie, PTX appears to eliminate all of the differences between the cellular responses to ß₁-ARs and ß₂-ARs). It has been speculated that ß₂-ARs induce a localized elevation in intracellular cAMP that activates only the adjacent L-type calcium channels at the plasma membrane and that the cAMP signal is broadcast throughout the cell after treatment with PTX. Although there is compelling evidence that ß-AR activation leads to a compartmentalized elevation of cAMP (only in the vicinity of the ß-AR) in frog ventricular myocytes,⁸⁵ studies of a possible molecular mechanism are still limited. The observation that calyculin A selectively enhances ß₂-AR–dependent (but not ß₁-AR–dependent) contractile responses has been taken as indirect evidence for ß₂-AR–dependent coupling via G_i to a protein phosphatase (which could account for the apparent PTX-dependent release of cAMP from the membrane to intracellular targets and the phosphorylation of PLB⁸⁵ ). However, a specific mechanism whereby inhibition of a protein phosphatase pathway by PTX would also lead to an increase in ß₂-AR affinity for agonists is not obvious.

ß₃-AR Actions in Cardiomyocytes
The ß₃-AR subtype has generated considerable interest as a potential target for antiobesity and antidiabetic drugs, because it activates thermogenesis and lipolysis in adipose tissue and regulates the physiological properties of the gastrointestinal tract. Recent studies provide persuasive evidence that ß₃-ARs are present in human cardiomyocytes. Here, in contrast to ß₁-ARs and ß₂-ARs, they have been implicated as inhibitors of contractile function.⁸⁶ The mechanism for the negative inotropic response appears to involve a PTX-sensitive G protein and the activation of a nitric oxide synthase pathway.⁸⁷ Although ß₃-ARs generally are not detected in rat cardiomyocytes, under certain experimental conditions (submaximal agonist concentrations, rapid pacing rates), the nonselective ß-AR agonist isoproterenol activates an endogenous NO pathway that blunts the ß-AR–dependent inotropic response.⁸⁸ These results suggest that a full analysis of catecholamine action must at least consider the possibility of an NO pathway and, at least in some species, a cardiac ß₃-AR subtype.

	Conclusions and Questions for Future Study

Top Introduction The {beta}-AR Complex: A... Distinct Signaling Pathways... Conclusions and Questions for... References

 
The profound developmental changes in the linkage of ß₂-ARs to effector response mechanisms in rat cardiomyocytes were summarized in the previous section to highlight several unanticipated features of ß-AR subtype signaling (which cannot be explained in the context of the traditional concepts of receptor-activated signaling pathways). These include (1) the age-dependent difference in the sensitivity of cardiac ß₂-ARs to agonist-induced activation, (2) the differential susceptibility of ß₁- and ß₂-AR–dependent cAMP accumulation to the inhibitory effects of carbachol in neonatal cardiomyocytes, and (3) the differences in the linkage of ß₁-AR and ß₂-AR to cAMP accumulation in adult cardiomyocytes. It is anticipated that a full understanding of the molecular mechanisms that underlie these intriguing complexities in the ß-AR subtype signaling pathways will require newer models that incorporate the potential for molecular heterogeneity of individual components of the ß-AR subtype signaling cascade as well as the concept that compartmentalization of second messenger molecules can facilitate and/or restrict receptor signaling events. Inquiries that address the questions in the section that follows should provide a better understanding of the functional significance of signals that are initiated at ß₂-ARs in cardiomyocytes.

What Is the Mechanism for ß₂-AR Signaling in Human Ventricular Cardiomyocytes: A cAMP-Dependent or cAMP-Independent Signaling Pathway?
Investigations of ß-AR subtype function in animal models are driven by the desire to identify the mechanism(s) for catecholamine action in normal and failing human cardiomyocytes. Against the conflicting backdrop, with a prominent cAMP-dependent pathway for ß₂-AR actions in neonatal but not in adult rat ventricular cardiomyocytes, results obtained in cardiomyocytes isolated from the ventricles of other mammalian species should be considered. Results of the rather limited literature describing the contribution of the ß₂-AR subtype to the contractile response are conflicting. The studies have been confined to adult myocardial tissues and demonstrate that the ß₂-AR induces a positive inotropic response via a cAMP-independent pathway in myocytes isolated from cat, dog, and sheep ventricles,^{89 90 91} whereas ß₂-ARs fail to regulate electrical activity in guinea pig ventricular myocytes,⁹² and there appears to be little in vivo ß₂-AR control of contractility in baboon myocardium (which is enriched in ß₂-ARs relative to other mammalian species).¹⁵ The validity of extrapolating data from any of these models to human ventricular cardiomyocytes remains uncertain. There is limited evidence that low concentrations of zinterol increase the amplitude of the calcium transient in myocytes from human ventricles that have failed as a result of several etiologies.⁹⁰ Zinterol also is reported to elicit positive inotropic and lusitropic responses in nonfailing human atrial tissue as a result of activation of a ß₂-AR pathway that involves cAMP accumulation, activation of PKA, and the phosphorylations of PLB, TNI, and C protein.⁹³ However, there is a difficulty inherent in using human atrial tissue as a surrogate for the normal human ventricle, given the numerous examples of atrial tissues retaining a phenotype that is more characteristic of the neonatal rather than the adult ventricle (in contrast to ventricular myocardium, in which many signaling pathways are downregulated during normal development and are recruited only in the context of a disease-associated recapitulation of the neonatal phenotype).

What Is the Mechanism(s) for Disordered Adrenergic Regulation in Congestive Heart Failure?
While sympathetic nervous system activation in heart failure may provide essential inotropic support, sustained adrenergic stimulation leads to desensitization. From studies on human tissues as well as a variety of animal models of experimental heart failure, there is general consensus that heart failure is associated with a constellation of changes in multiple components of the ß-AR complex. At the level of the receptor, the ß₁-AR subtype is downregulated (at the protein and mRNA levels), whereas ß₂-AR expression is preserved.^{3 4 94 95} Although results of in vitro biochemical assays on membranes from normal hearts are compatible with the conclusion that human ß₂-ARs couple to G_s more efficiently than ß₁-ARs,⁴ the coupling of both ß-AR subtypes to G_s reportedly is impaired in human heart failure. This is presumed to result from a selective upregulation of certain myocardial forms of GRK (GRK2 [ßARK1] and/or GRK5, as changes in GRK3 [ßARK2] or ß-arrestin are not detected), which in at least one experimental model coincides with receptor uncoupling and precedes any ß-AR downregulation.^{56 96 97} Thus, the conventional paradigm holds that ß₂-ARs assume a greater importance in mediating the inotropic and chronotropic responses to the increased sympathetic drive (and/or exogenous agonists) in the context of heart failure. In this context, recent studies have considered in the analysis a polymorphism of the ß₂-AR in the human population that may represent a disease modifier. Specifically, of the 4 changes in the coding sequence of the ß₂-AR gene (from what has been designated the wild type) that have been identified, the Ile164 ß₂-AR variant (where Ile is substituted for Thr at position 164 in the fourth TMD) is detected in 6% to 8% of the population. This variant, when overexpressed in a fibroblast cell line, is substantially uncoupled from G_s⁹⁸ ; when overexpressed in the hearts of transgenic mice, the function of the Ile164 variant is substantially impaired.⁹⁹ According to a recent study, this polymorphism does not predispose to heart failure, but individuals with heart failure harboring this receptor are at significant risk for rapid decompensation.¹⁰ Further studies to determine whether the more common polymorphisms at the 16 and 27 positions (which differ in their downregulation phenotypes) also may underlie interindividual variations in catecholamine responsiveness in the population are warranted.

Studies of G proteins have focused on the subunit and tend to show increased levels of _i, without any abnormalities in _s expression.¹⁰⁰ To date, molecular analyses of the AC enzyme have been confined to pacing-induced heart failure models, in which the mRNAs for the type V and/or type VI enzymes tend to be reduced.⁵⁶ Assuming that this is associated with a reduction in the cognate proteins, the prediction is that this would lead to a significant impairment in transmembrane ß-AR signaling. This prediction is based on recent evidence that the abundance of the AC protein (a relatively sparse membrane protein) sets the limit on transmembrane ß-AR signaling.⁶⁴ Thus, the changes in the context of heart failure collectively would act to impair signaling via the excitatory ß₁- and ß₂-ARs. In this context, it has recently been speculated that the inhibitory, desensitization-resistant ß₃-AR might couple to the upregulated pool of inhibitory G_i proteins and assume increased importance in the failing heart.¹⁰¹

Does Chronic Activation of ß-ARs Lead to Cardiomyocyte Hypertrophy and/or Injury?
A pressing clinical question, and the subject of considerable recent controversy, has been whether the depressed AR response in the failing heart represents a convenient target for therapeutic intervention or whether maneuvers that increase neurohumoral activation will contribute to the progression of heart failure and should be avoided. In the context of the known ability of various G protein–coupled receptors to influence hypertrophic cell growth and/or the decision to undergo apoptosis in cardiomyocytes,^{102 103 104 105 106} there has been an almost singular focus on the ₁-AR as a mediator of catecholamine-induced growth-promoting pathways in the heart; a possible ß-AR component has largely been ignored. However, there is consistent evidence that ß-ARs induce protooncogene (c-fos, c-jun) and ANF expression and stimulate protein synthesis in cardiomyocytes (although the extent to which this includes the synthesis of contractile proteins required for sarcomerogenesis has been the subject of controversy).^{107 108 109 110} The mechanism for the growth-regulatory properties of cardiac ß-ARs has not been identified definitively. There is evidence that ß-ARs induce ANF through a calcium-dependent (cAMP-independent) signaling mechanism.¹¹⁰ Calcium-dependent kinases and phosphatases have been implicated in pathways leading to transcriptional activation and/or hypertrophic growth responses in cardiomyocytes^{111 112 113 114} ; their individual or combinatorial actions could provide the link between alterations in cardiomyocyte calcium handling and hypertrophic growth responses. Alternatively, other studies identify a link between ß-ARs and a cascade that involves Raf-1 kinase and the ERK subfamily of mitogen-activated protein kinases in cardiomyocytes^{115 116} (a somewhat surprising result, given that cAMP-dependent activation of PKA generally blocks activation of Raf-1 in other cell types^{117 118} ). Although activation of the ERK cascade has been implicated in the pathway that promotes cell survival in neonatal cardiomyocytes,^{105 106} the importance of this mechanism in adult cardiomyocytes is uncertain given the recent reports that norepinephrine stimulates apoptosis via a ß₁-AR (and not ß₂-AR) pathway that involves PKA and calcium entry through L-type calcium channels in adult cardiomyocytes.¹¹⁹ Finally, it is possible that a ß₃-AR pathway leading to the production of NO (which has been reported to influence the propensity to undergo apoptosis) will figure in the analysis of catecholamine actions in the human heart.^{87 120 121 122}

Transgenic mice that selectively overexpress individual ß-AR subtypes as well as various downstream components of their signaling pathways (G_s, AC) have been generated in an attempt to determine the physiological consequences of chronic sympathetic drive to the heart.^{19 99 123 124 125} ß₂-AR overexpression at high levels (50- to 200-fold greater than total ß-AR expression in nontransgenic mice) enhances basal AC activity and provides inotropic support (baseline cardiac function in these transgenic mice is elevated to levels characteristic of control animals treated with isoproterenol).¹⁹ Because long-term toxic effects to the heart have not been reported for this model,^{19 99} it has been suggested that maneuvers that serve to augment ß-AR signaling (ultimately including in vivo gene transfer strategies) may represent a viable, therapeutic option for patients suffering from congestive heart failure. This formulation is consistent with evidence that the contractility of single myocytes isolated from the ventricles of rabbits chronically paced to produce heart failure can be restored by adenovirus-mediated transfer of the ß₂-AR.¹²⁶ However, these results have been difficult to reconcile with clinical studies in patients, which on balance suggest that ß-AR blockade (rather than inotropic therapy with sympathomimetic amines) is beneficial in heart failure.^{127 128} In this context, the rather different results obtained in transgenic mice that overexpress ß₁-ARs (at levels only 5- to 15-fold greater than normal) or G_s should be noted. Here, an initial transient increased cardiac function is followed by progressive cardiac deterioration as the animals age (with histological features of cardiomyocyte necrosis, replacement fibrosis, and compensatory hypertrophy of other myocytes, and physiological evidence of reduced left ventricular contractile function and—in mice that overexpress G_s—arrhythmias and increased mortality).^{129 130} In an attempt to resolve this apparent inconsistency in the literature, newer lines of transgenic mice that overexpress ß₂-ARs over a range of levels have been generated. These studies provide evidence that ß₂-AR overexpression at very high levels or protracted durations is deleterious (ie, chronic drive through either ß₁-ARs or ß₂-ARs can lead to a cardiomyopathy; S.B. Liggett, personal communication, August 1999). Nevertheless, the therapeutic window for ß₂-ARs appears to be much broader than for ß₁-ARs. Moreover, studies to determine whether the biological features of ß₁-AR and ß₂-AR overexpression become even more prominent when these mice are subjected to pathologic insults are ongoing in several laboratories. In the context of efforts to determine whether ß₁- and ß₂-ARs display functionally significant intrinsic differences in their signaling and/or desensitization properties (such as those described in this review), these studies will yield crucial information regarding the pathophysiologic significance of chronic stimulation of individual ß-AR subtypes in the development (and potentially therapy) of hypertrophic and/or degenerative changes in the failing heart.

	Acknowledgments

 
This work was supported by U.S.P.H.S.-N.H.L.B.I. grant HL-28958. The author would like to thank Dr Richard Robinson for the close working relationship that led to many insightful discussions during the course of investigations cited in this review. The author also thanks the members of her laboratory who contributed to the work presented in this review.

Received March 3, 1999; accepted September 15, 1999.

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