Review article
β-Adrenergic receptor signaling in the heart: Role of CaMKII

https://doi.org/10.1016/j.yjmcc.2009.10.016Get rights and content

Abstract

The multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) targets a number of Ca2+ homeostatic proteins and regulates gene transcription. Many of the substrates phosphorylated by CaMKII are also substrates for protein kinase A (PKA), the best known downstream effector of β-adrenergic receptor (β-AR) signaling. While PKA and CaMKII are conventionally considered to transduce signals through separate pathways, there is a body of evidence suggesting that CaMKII is activated in response to β-AR stimulation and that some of the downstream effects of β-AR stimulation are actually mediated by CaMKII. The signaling pathway through which β-AR stimulation activates CaMKII, in parallel with or downstream of PKA, is not well-defined. This review considers the evidence for and mechanisms by which CaMKII is activated in response to β-AR stimulation. In addition the potential role of CaMKII in β-AR regulation of cardiac function is considered. Notably, although many CaMKII targets (e.g., phospholamban or the ryanodine receptor) are central to the regulation of Ca2+ handling, and effects of CaMKII on Ca2+ handling are detectable, inhibition or gene deletion of CaMKII has relatively little effect on the acute physiological contractile response to β-AR. On the other hand CaMKII expression and activity are increased in heart failure, a pathophysiological condition characterized by chronic stimulation of cardiac β-ARs. Blockade of β-ARs is an accepted therapy for treatment of chronic heart failure although the rationale for its beneficial effects in cardiomyocytes is uncertain. There is growing evidence that inhibition or gene deletion of CaMKII also has a significant beneficial impact on the development of heart failure. The possibility that excessive β-AR stimulation is detrimental because of its effects on CaMKII mediated Ca2+ handling disturbances (e.g., ryanodine receptor phosphorylation and diastolic SR Ca2+ leak) is an intriguing hypothesis that merits future consideration.

Introduction

Sympathetic stimulation of cardiac β1-adrenergic receptors (β-AR) induces positive inotropic and chronotropic effects—the so-called “fight or flight response,” the most effective mechanism to acutely increase output of the heart. Cyclic AMP (cAMP) formed through β-AR mediated activation of adenylyl cyclase (AC), and the subsequent activation of its downstream target, the cAMP dependent protein kinase (PKA), are well-described mediators with targets that promote maximal myocardial performance. Excessive sympathetic nervous system activity observed in heart failure can cause detrimental effects such as cardiomyocyte death [1], [2], [3], and β-AR blockers are one of the standard therapeutic approaches for the treatment of chronic heart failure. In many ways, however, the rationale for the salutary effects of β-AR blockade in heart failure treatment appears paradoxical since these agents further reduce contractile performance by reducing inotropic and chronotropic effects of catecholamines. Promising new therapeutic strategies for heart failure will most likely result from better understanding of downstream effectors of β-AR signaling which allow one to separate beneficial from detrimental pathways. For example, stimulation of β-AR activates the two most abundant AC types 5 and 6 in the heart to produce cAMP, but they appear to have opposite effects, with AC5 activity being detrimental [4] and AC6 being beneficial [5] for heart function. Other studies have suggested that downregulation of β-AR in heart failure–generally thought to be an adaptive and protective mechanism and one that should in theory mimic β-AR blockade–is maladaptive [6], [7]. Inhibition of myocardial β-AR desensitization, using in vivo intracoronary adenoviral-mediated gene delivery of a peptide inhibitor of β-AR kinase (βARK1), was shown to improve cardiac function and prevent the development of heart failure in rabbit hearts subjected to myocardial infarction [6] or reverse cardiac dysfunction [7], suggesting that enhancing rather than blocking β-AR signaling has salutary effects.

Interestingly and perhaps one reason for the discrepancies above, not all downstream elements of the β-AR pathway are targets of the well established β-AR/cAMP/PKA signaling cascade. More than a decade ago, Baltas et al. [8] published the unexpected and still relatively unappreciated finding that β-AR stimulation activates Ca2+/calmodulin dependent protein kinase (CaMK) II in the intact beating heart. The authors' conclusion was based on measurement of CaMKII autophosphorylation and phosphorylation of the CaMKII target phospholamban (PLN) in Langendorff-perfused rat hearts. Subsequently a substantial body of literature using different systems and endpoints has documented the involvement of CaMKII in mediating effects of β-AR stimulation on phosphorylation of Ca2+ handling proteins [9], [10], [11], Ca2+ release from the sarcoplasmic reticulum [10], [12], contractility [13], hypertrophic gene expression [14], and apoptosis [2]. In contrast to our extensive knowledge regarding molecular events in the β-AR/cAMP/PKA signaling cascade, the mechanism by which stimulation of the β-AR results in CaMKII activation and the role of CaMKII in β-AR are not generally appreciated and poorly understood. Here we review evidence that a significant component of β-AR signaling is mediated through CaMKII, suggest that this pathway is particularly prominent under pathophysiological conditions, and consider whether the beneficial effects of β-AR blockade in heart failure might be explained by attenuation of CaMKII signaling. Interestingly, the effect of β-blocker therapy on the expression or activity of CaMKII in chronic heart failure has never been explored.

Section snippets

Assessment of CaMKII activity

Essential to the hypothesis that CaMKII mediates the effects of β-AR stimulation is demonstrating that CaMKII is activated in response to β-adrenergic stimulation (Fig. 1). It is possible to measure the enzymatic activity of CaMKII and activation state using specific substrates and addition of its regulators, Ca2+and calmodulin, and this direct approach has in fact been used in some studies [2], [15], [16], [17], [18]. An alternative is to examine the autophosphorylation of the enzyme at

CaMKII targets in β-adrenergic signaling

Norepinephrine stimulates postsynaptic β-ARs in the heart resulting in positive chronotropic (heart beats faster), positive inotropic (heart beats stronger), and positive lusitropic (heart relaxes faster) response. Calcium plays a crucial role in regulating these β-adrenergic effects. As described above, Ca2+ enters the myocyte via the LTCC, which triggers the release of Ca2+ ions from the SR via calcium release channels (RyR). Re-uptake of Ca2+ into the SR occurs via SERCA and is regulated by

Role of CaMKII in β-AR signaling

Acute β-adrenergic activation causes the “fight-or-flight” response that makes the heart beat faster and stronger. Chronic β-adrenergic activation as observed in heart failure results in desensitization of β-adrenergic signaling with a decreased fight-or-flight response (i.e., exercise intolerance) and detrimental changes including hypertrophy, apoptosis and arrhythmias.

Conclusion

CaMKII is a multifunctional signaling molecule that is abundant in the heart and activated by β-AR stimulation. CaMKII targets cytoplasmic proteins important for Ca2+ handling such as PLN and the RyR but also transduces Ca2+ signals into the nucleus to regulate gene transcription. Chronic inhibition or gene deletion of CaMKII appear to have little effect on basal function of the heart or on acute responses to β-adrenergic stimulation but have a significant beneficial impact on cardiac function

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