What role does modulation of the ryanodine receptor play in cardiac inotropy and arrhythmogenesis?

Eisner, David; Kashimura, Takeshi; O’Neill, Stephen; Venetucci, Luigi; Trafford, Andrew W.

doi:10.1016/j.yjmcc.2008.12.005

Cited by 85 publications

(68 citation statements)

References 83 publications

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“…Since, in these cells I Ca,L regulation was normal, the augmented ECC in Pde4d -/-myocytes could be related to PKA hyperphosphorylation of RyR2 during β-AR stimulation and increased open probability of the Ca 2+ release channel (8,29). However, increasing RyR activity alone may not be sufficient to explain an increase in Ca 2+ transient amplitude (38), especially because such phenomenon can result ultimately in a decreased SR Ca 2+ content (39,40). PLB mediates part of the positive inotropic effect of β-AR stimulation by increasing SR Ca 2+ load (41, 42).…”

Section: Discussionmentioning

confidence: 95%

Phosphodiesterase 4B in the cardiac L-type Ca2+ channel complex regulates Ca2+ current and protects against ventricular arrhythmias in mice

Leroy¹,

Richter²,

Mika³

et al. 2011

J. Clin. Invest.

114

123

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(PDEs) regulate local cAMP concentration in cardiomyocytes, with PDE4 being predominant for the control of β-AR-dependent cAMP signals. Three genes encoding PDE4 are expressed in mouse heart: Pde4a, Pde4b, and Pde4d. Here we show that both PDE4B and PDE4D are tethered to the LTCC in the mouse heart but that β-AR stimulation of the L-type Ca 2+ current (I Ca,L ) is increased only in Pde4b -/-mice. A fraction of PDE4B colocalized with the LTCC along T-tubules in the mouse heart. Under β-AR stimulation, Ca 2+ transients, cell contraction, and spontaneous Ca 2+ release events were increased in Pde4b -/-and Pde4d -/-myocytes compared with those in WT myocytes. In vivo, after intraperitoneal injection of isoprenaline, catheter-mediated burst pacing triggered ventricular tachycardia in Pde4b -/-mice but not in WT mice. These results identify PDE4B in the Ca V 1.2 complex as a critical regulator of I Ca,L during β-AR stimulation and suggest that distinct PDE4 subtypes are important for normal regulation of Ca 2+ -induced Ca 2+ release in cardiomyocytes. IntroductionDuring the cardiac action potential, Ca 2+ influx through sarcolemmal L-type Ca 2+ channels (LTCCs) triggers Ca 2+ release from juxtaposed ryanodine receptor 2 (RyR2) located in the sarcoplasmic reticulum (SR). This allows a rapid and synchronous Ca 2+ elevation throughout the cell, which activates contraction. During cardiac relaxation, Ca 2+ is rapidly extruded by the Na + /Ca 2+ exchanger and re-sequestered into the SR by the Ca 2+ -ATPase, SERCA2 (1). This process is highly regulated, in particular, by the sympathetic nervous system. β-Adrenergic receptors (β-ARs) exert strong inotropic and lusitropic effects by increasing intracellular cAMP levels and activating cAMP-dependent PKA. PKA then phosphorylates the key proteins of the excitation-contraction coupling (ECC) process, including LTCC and RyR2 but also phospholamban (PLB), which controls Ca 2+ reuptake by SERCA2, as well as the myofilament proteins troponin I and myosin binding protein C (1).The cardiac LTCC consists of the central pore-forming subunit α 1C (Ca V 1.2) and auxiliary β and α 2 -δ subunits that modulate its function (2). Upon β-AR stimulation, phosphorylation of Ca V 1.2, the auxiliary β 2 subunit, or the closely associated protein AHNAK by PKA increases channel activity, thus enhancing the L-type Ca 2+ current (I Ca,L ) (3-5). This regulation involves physical

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Section: Discussionmentioning

confidence: 95%

Phosphodiesterase 4B in the cardiac L-type Ca2+ channel complex regulates Ca2+ current and protects against ventricular arrhythmias in mice

Leroy¹,

Richter²,

Mika³

et al. 2011

J. Clin. Invest.

114

123

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“…In this model, hyperphosphorylation of RyR2 at Ser2815 increases the propensity toward spontaneous Ca 2+ release from the SR, which, if it happened as an isolated event, would quickly lead to depletion of the SR and suspension of Ca 2+ release events (29). However, simultaneous hyperphosphorylation of PLB would promote fast refilling of the SR, thereby supporting a continuous SR Ca 2+ leak, which may lead to delayed afterdepolarizations, triggered activity, and ventricular arrhythmias.…”

Section: Discussionmentioning

confidence: 99%

Constitutively active phosphatase inhibitor-1 improves cardiac contractility in young mice but is deleterious after catecholaminergic stress and with aging

Wittköpper

Fabritz²,

Neef³

et al. 2010

J. Clin. Invest.

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Phosphatase inhibitor-1 (I-1) is a distal amplifier element of β-adrenergic signaling that functions by preventing dephosphorylation of downstream targets. I-1 is downregulated in human failing hearts, while overexpression of a constitutively active mutant form (I-1c) reverses contractile dysfunction in mouse failing hearts, suggesting that I-1c may be a candidate for gene therapy. We generated mice with conditional cardiomyocyterestricted expression of I-1c (referred to herein as dTG I-1c mice) on an I-1-deficient background. Young adult dTG I-1c mice exhibited enhanced cardiac contractility but exaggerated contractile dysfunction and ventricular dilation upon catecholamine infusion. Telemetric ECG recordings revealed typical catecholamine-induced ventricular tachycardia and sudden death. Doxycycline feeding switched off expression of cardiomyocyterestricted I-1c and reversed all abnormalities. Hearts from dTG I-1c mice showed hyperphosphorylation of phospholamban and the ryanodine receptor, and this was associated with an increased number of catecholamine-induced Ca 2+ sparks in isolated myocytes. Aged dTG I-1c mice spontaneously developed a cardiomyopathic phenotype. These data were confirmed in a second independent transgenic mouse line, expressing a full-length I-1 mutant that could not be phosphorylated and thereby inactivated by PKC-α (I-1 S67A ). In conclusion, conditional expression of I-1c or I-1 S67A enhanced steady-state phosphorylation of 2 key Ca 2+ -regulating sarcoplasmic reticulum enzymes. This was associated with increased contractile function in young animals but also with arrhythmias and cardiomyopathy after adrenergic stress and with aging. These data should be considered in the development of novel therapies for heart failure. IntroductionHeart failure is among the most frequent causes of morbidity and mortality worldwide and is, despite improved treatment options, associated with poor prognosis. Current treatment with angiotensin-converting enzyme inhibitors, aldosterone receptor antagonists, and beta blockers is suboptimal, with the 5-year survival rate being less than 50%. New drug principles targeting neurohumoral activation mechanisms, such as antagonists of endothelin receptors, TNF-α or IL-6, and statins, failed to improve survival in clinical studies. Thus, new approaches are needed, and an attractive one is to target the abnormal function of cardiomyocytes in failing hearts directly (as opposed to the more indirect affection by neurohumoral blockade).Two of the best studied alterations of failing myocyte function are (a) desensitization of the β-adrenergic signaling system (1, 2) and (b) alterations of intracellular Ca 2+ handling (3, 4). The latter include decreased diastolic sarcoplasmic reticulum (SR) Ca 2+ uptake via the SR Ca 2+ ATPase (SERCA2a) and relatively increased

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“…Eisner and Trafford 32 have demonstrated that changes in RyR2 Ca sensitivity (eg, by caffeine) have only transient effects on systolic function due to a sort of autoregulation. That is, the first beat with higher Ca sensitivity does have greater SR Ca release, but that drives greater Ca extrusion from the cell via Na/Ca exchange, such that SR Ca uptake and content progressively decrease over a few beats.…”

Section: Does Enhanced Sr Ca Leak In Hf Contribute To Dysfunction?mentioning

confidence: 99%

Ryanodine Receptor S2808 Phosphorylation in Heart Failure

Bers

2012

Circulation Research

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What role does modulation of the ryanodine receptor play in cardiac inotropy and arrhythmogenesis?

Cited by 85 publications

References 83 publications

Phosphodiesterase 4B in the cardiac L-type Ca2+ channel complex regulates Ca2+ current and protects against ventricular arrhythmias in mice

Phosphodiesterase 4B in the cardiac L-type Ca2+ channel complex regulates Ca2+ current and protects against ventricular arrhythmias in mice

Constitutively active phosphatase inhibitor-1 improves cardiac contractility in young mice but is deleterious after catecholaminergic stress and with aging

Ryanodine Receptor S2808 Phosphorylation in Heart Failure

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