The cAMP binding protein Epac modulates Ca<sup>2+</sup> sparks by a Ca<sup>2+</sup>/calmodulin kinase signalling pathway in rat cardiac myocytes

Pereira, Laëtitia; Métrich, Mélanie; Fernández‐Velasco, María; Lucas, Alexandre; Leroy, Jérôme; Perrier, Romain; Morel, Éric; Fischmeister, Rodolphe; Richard, Sylvain; Bénitah, Jean‐Pierre; Lezoualc’h, Frank; Gómez, Ana M.

doi:10.1113/jphysiol.2007.133066

Cited by 183 publications

(252 citation statements)

References 39 publications

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“…Recently, it has been shown that β-AR stimulation can also induce PKA-independent, i.e., CaMKII-or EPAC-mediated SR Ca 2+ leakage in vitro by increasing RyR2 phosphorylation on serine-2814/2815 and PLN phosphorylation on threonine-17 via PLCε/PLCε/CaMKII signaling (27)(28)(29)(30)55). Nevertheless, key functional issues remain to be clarified because most previous studies relied on pharmacological stimulation with 8-CPT, an EPAC-selective but not isoformselective cAMP analogue, which could have off-target effects (37).…”

Section: Discussionmentioning

confidence: 99%

Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses

Okumura¹,

Fujita²,

Cai³

et al. 2014

J. Clin. Invest.

148

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PKA phosphorylates multiple molecules involved in calcium (Ca 2+ ) handling in cardiac myocytes and is considered to be the predominant regulator of β-adrenergic receptor-mediated enhancement of cardiac contractility; however, recent identification of exchange protein activated by cAMP (EPAC), which is independently activated by cAMP, has challenged this paradigm. Mice lacking Epac1 (Epac1 KO) exhibited decreased cardiac contractility with reduced phospholamban (PLN) phosphorylation at serine-16, the major PKA-mediated phosphorylation site. In Epac1 KO mice, intracellular Ca 2+ storage and the magnitude of Ca 2+ movement were decreased; however, PKA expression remained unchanged, and activation of PKA with isoproterenol improved cardiac contractility. In contrast, direct activation of EPAC in cardiomyocytes led to increased PLN phosphorylation at serine-16, which was dependent on PLC and PKCε. Importantly, Epac1 deletion protected the heart from various stresses, while Epac2 deletion was not protective. Compared with WT mice, aortic banding induced a similar degree of cardiac hypertrophy in Epac1 KO; however, lack of Epac1 prevented subsequent cardiac dysfunction as a result of decreased cardiac myocyte apoptosis and fibrosis. Similarly, Epac1 KO animals showed resistance to isoproterenol-and aging-induced cardiomyopathy and attenuation of arrhythmogenic activity. These data support Epac1 as an important regulator of PKA-independent PLN phosphorylation and indicate that Epac1 regulates cardiac responsiveness to various stresses.

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Section: Discussionmentioning

confidence: 99%

Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses

Okumura¹,

Fujita²,

Cai³

et al. 2014

J. Clin. Invest.

148

View full text Add to dashboard Cite

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“…Whereas CaMKII is directly regulated by Ca 2+ , its activity is indirectly regulated by cAMP (9). In response to βAR stimulation, Epac (Exchange Protein directly Activated by cAMP) activates CaMKII (10)(11)(12)(13)(14). This regulation is critical in pathophysiological conditions in which CaMKII expression and activation may be elevated, such as hypertrophy, heart failure, and arrhythmias (2,3).…”

mentioning

confidence: 99%

A CaMKII/PDE4D negative feedback regulates cAMP signaling

Mika

Richter

Conti

2015

Proc. Natl. Acad. Sci. U.S.A.

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cAMP production and protein kinase A (PKA) are the most widely studied steps in β-adrenergic receptor (βAR) signaling in the heart; however, the multifunctional Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is also activated in response to βAR stimulation and is involved in the regulation of cardiac excitation-contraction coupling. Its activity and expression are increased during cardiac hypertrophy, in heart failure, and under conditions that promote arrhythmias both in animal models and in the human heart, underscoring the clinical relevance of CaMKII in cardiac pathophysiology. Both CaMKII and PKA phosphorylate a number of protein targets critical for Ca 2+ handling and contraction with similar, but not always identical, functional consequences. How these two pathways communicate with each other remains incompletely understood, however. To maintain homeostasis, cyclic nucleotide levels are regulated by phosphodiesterases (PDEs), with PDE4s predominantly responsible for cAMP degradation in the rodent heart. Here we have reassessed the interaction between cAMP/PKA and Ca 2+ /CaMKII signaling. We demonstrate that CaMKII activity constrains basal and βAR-activated cAMP levels. Moreover, we show that these effects are mediated, at least in part, by CaMKII regulation of PDE4D. This regulation establishes a negative feedback loop necessary to maintain cAMP/CaMKII homeostasis, revealing a previously unidentified function for PDE4D as a critical integrator of cAMP/PKA and Ca elevation throughout the cell promotes myofilament sliding, which generates contractile force. This process is highly regulated by positive and negative regulatory circuits, the most critical being the sympathetic nervous system that acts via activation of the β-adrenergic (βAR)/cAMP/PKA signaling pathway. During βAR stimulation, PKA phosphorylates and activates key proteins involved in ECC and Ca 2+ handling. These proteins include L-type Ca 2+ channels and ryanodine receptors (RyR), leading to enhanced Ca 2+ influx and consequent sarcoplasmic reticulum (SR) Ca 2+ release; phospholamban (PLB), increasing SR Ca 2+ uptake by the Ca 2+ ATPase (SERCA), thereby accelerating cardiac relaxation; and contractile proteins, increasing cell contraction. Collectively, these events produce the typical inotropic and lusitropic effects of βAR stimulation (1).This βAR/cAMP/PKA pathway is only one of the components involved in regulating cardiac function, however. Data accumulated in the last decade have revealed that Ca 2+

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“…Ainsi, la protéine Epac1, du réticulum sarcoplasmique [33,34]. Il a été proposé que l'augmentation du relargage ectopique de calcium, consécutive à l'activation de Epac par les -AR, pourrait être à l'origine des effets arythmogènes dans les cardiomyocytes isolés de souris.…”

Section: Resultsunclassified

Les acteurs moléculaires du remodelage cardiaque pathologique

et al. 2015

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> L'exercice physique ou l'hypertension artérielle sont deux situations, l'une physiologique, l'autre pathologique, au cours desquelles le coeur augmente son travail hémodynamique. Cette adaptation repose sur un remodelage cardiaque différent selon la nature physiologique ou pathologique du stress. Illustrée par deux exemples, l'étude des événements moléculaires aboutissant au remodelage cardiaque offre de nouvelles opportunités pour le développement de thérapies de l'insuffisance cardiaque. Récemment décrite, la protéine Epac1 est un relais du second messager AMPc. À la suite d'un stress pathologique, la mise en évidence de ses rôles dans l'hypertrophie, la fibrose cardiaque et l'altération du cycle calcique suggère que son inhibition pharmacologique peut présenter un intérêt thérapeutique. Carabin est une nouvelle protéine régulatrice de plusieurs effecteurs moléculaires impliqués dans le remodelage cardiaque pathologique. La manipulation expérimentale de son expression modifie profondément le développement de l'insuffisance cardiaque. < du travail cardiaque [1]. Ce remodelage permet de prendre en charge l'augmentation de la perfusion des organes nécessaire dans ces conditions physiologiques. Le remodelage cardiaque pathologique est observé en association avec différentes pathologies, familiales ou acquises, dont les plus répandues sont l'hypertension artérielle, l'infarctus du myocarde et les troubles du métabolisme. La qualification de pathologique du remodelage, initialement sans conséquences cliniques, repose sur son association avec la survenue ultérieure de pathologies cardiovasculaires. Le remodelage pathologique comprend de multiples atteintes dont les mieux décrites sont la modification de la géométrie de la cavité cardiaque associée à une hypertrophie des cellules contractiles cardiaques (les cardiomyocytes), en particulier dans le sens longitudinal, la fibrose et l'altération de la force contractile cardiaque provenant de modifications diverses du couplage excitation-contraction [2] (Figure 1). Il est à noter que des modifications d'autres tissus (artériels, nerveux, musculaires ou ceux impliqués dans le métabolisme) peuvent participer au dévelop-pement de l'insuffisance cardiaque (IC), mais nous n'abordons ici que le remodelage du tissu cardiaque. Ces altérations concourent à la mise en place du syndrome clinique d'insuffisance cardiaque lorsque le fonctionnement du coeur n'assure plus la perfusion adéquate des organes [41] (➜). Le remodelage cardiaque pathologique a été identifié comme une cible thérapeutique potentielle à partir d'une étude prospective 1 Inserm, UMR-1048, institut des maladies métaboliques et cardiovasculaires,

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The cAMP binding protein Epac modulates Ca²⁺ sparks by a Ca²⁺/calmodulin kinase signalling pathway in rat cardiac myocytes

Cited by 183 publications

References 39 publications

Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses

Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses

A CaMKII/PDE4D negative feedback regulates cAMP signaling

Les acteurs moléculaires du remodelage cardiaque pathologique

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The cAMP binding protein Epac modulates Ca2+ sparks by a Ca2+/calmodulin kinase signalling pathway in rat cardiac myocytes

Cited by 183 publications

References 39 publications

Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses

Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses

A CaMKII/PDE4D negative feedback regulates cAMP signaling

Les acteurs moléculaires du remodelage cardiaque pathologique

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Product

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The cAMP binding protein Epac modulates Ca²⁺ sparks by a Ca²⁺/calmodulin kinase signalling pathway in rat cardiac myocytes