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