PKA Phosphorylation Dissociates FKBP12.6 from the Calcium Release Channel (Ryanodine Receptor)

Marx, Steven O.; Reiken, Steven; Hisamatsu, Yosuke; Jayaraman, Thottala; Burkhoff, Daniel; Rosemblit, Nora; Marks, Andrew R.

doi:10.1016/s0092-8674(00)80847-8

Cited by 1,874 publications

(2,305 citation statements)

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“…A major deficit in failing myocytes is the reduced Ca 2+ content of the SR, which is related to decreased expression and activity of the SR Ca 2+ -ATPase [84,92,146,153] and an increased Ca 2+ leak of the RyR2 due to hyperphosphorylation [84,94,112,122]. These defects, potentially aggravated by L-type Ca 2+ channel dysfunction [41,71,81,86,113,131,146,184] or t-tubular derangement [32,86,115,145,184], lead to a smaller and more dyssynchronous SR Ca 2+ release during an AP, resulting in slower rates of increase and decay of [Ca 2+ ] c , but higher diastolic [Ca 2+ ] c compared to normal cardiac myocytes [17,81,113,115,146,184].…”

Section: Pathophysiological Aspects Defects In Ec Coupling In Chronicmentioning

confidence: 99%

Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

221

183

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Cardiac excitation-contraction (EC) coupling consumes vast amounts of cellular energy, most of which is produced in mitochondria by oxidative phosphorylation. In order to adapt the constantly varying workload of the heart to energy supply, tight coupling mechanisms are essential to maintain cellular pools of ATP, phosphocreatine and NADH. To our current knowledge, the most important regulators of oxidative phosphorylation are ADP, P i , and Ca 2+ . However, the kinetics of mitochondrial Ca 2+ -uptake during EC coupling are currently a matter of intense debate. Recent experimental findings suggest the existence of a mitochondrial Ca 2+ microdomain in cardiac myocytes, justified by the close proximity of mitochondria to the sites of cellular Ca 2+ release, i. e., the ryanodine receptors of the sarcoplasmic reticulum. Such a Ca 2+ microdomain could explain seemingly controversial results on mitochondrial Ca 2+ uptake kinetics in isolated mitochondria versus whole cardiac myocytes. Another important consideration is that rapid mitochondrial Ca 2+ uptake facilitated by microdomains may shape cytosolic Ca 2+ signals in cardiac myocytes and have an impact on energy supply and demand matching. Defects in EC coupling in chronic heart failure may adversely affect mitochondrial Ca 2+ uptake and energetics, initiating a vicious cycle of contractile dysfunction and energy depletion. Future therapeutic approaches in the treatment of heart failure could be aimed at interrupting this vicious cycle. Keywords calcium; sodium; microdomain; heart failure; adenosine triphosphate; adenosine diphosphate; respiration; tricarboxylic acid cycle Physiological aspectsThe most important function of the heart is to pump blood to supply the body with oxygen and substrates. In order to adapt cardiac output to the constantly changing demand of blood supply, the heart utilizes three major mechanisms to increase cardiac output: the force-frequency relationship (the Bowditch effect or Treppe; [22]), the Frank-Starling mechanism (sarcomere length-dependent activation of contractile force) [66,149,164], and sympathetic activation [28]. All of these mechanisms increase and accelerate myocardial force generation, and at the same time increase cellular energy demand. By these mechanisms, cardiac output during exertion can be increased more than five-fold compared to resting conditions. © Steinkopff Verlag 2007Correspondence to: Christoph Maack. NIH Public Access Excitation-contraction couplingOf fundamental importance for cardiac contraction and relaxation are the processes of excitation-contraction (EC) coupling (Fig. 1). During the action potential (AP), voltage-gated Na + -channels are activated, and the inward Na + -current (I Na ) induces a rapid depolarization of the cell membrane, facilitating voltage-dependent opening of L-type Ca 2+ -channels (I Ca,L ). The Ca 2+ influx triggers the opening of the ryanodine receptor (RyR2 subtype), inducing the release of even greater amounts of Ca 2+ from the sarcoplasmic reticulum (SR), a process te...

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Section: Pathophysiological Aspects Defects In Ec Coupling In Chronicmentioning

confidence: 99%

Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

221

183

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“…Even though circulating levels of catecholamines are constitutively higher than in healthy persons, beta-adrenergic receptors appear to be down-regulated, and the robust responsiveness to agents such as isoproterenol seen in healthy heart cells is severely attenuated (Marks, 2001;Chien et al, 2003). Biochemical studies have indicated that this abnormal, sustained "hyperadrenergic" state leads to excess phosphorylation of RyRs (Marx et al, 2000), although this result remains controversial (Jiang et al, 2002). Complementary planar lipid bilayer studies of RyR gating have predicted that this hyperphosphorylation will lead to increased RyR open probability.…”

Section: The Paradoxmentioning

confidence: 99%

“…Complementary planar lipid bilayer studies of RyR gating have predicted that this hyperphosphorylation will lead to increased RyR open probability. Additional key results are that RyR phosphorylation causes dissociation of FKBP12.6 from the RyR macromolecular complex (Marx et al, 2000) and that in HF RyRs display decreased binding to this regulatory protein (Ono et al, 2000). Together, one might expect that these effects would lead to increased Ca 2+ leak from the SR and an increased rate of Ca 2+ sparks in quiescent ventricular myocytes isolated from failing hearts.…”

Section: The Paradoxmentioning

confidence: 99%

“…Recent findings have led to an increased appreciation of the complexity of the regulatory elements as the molecular details that underlie the regulation unfold (Cheng et al, 1993;Gomez et al, 1997;Marx et al, 2000;Pogwizd et al, 2001;Trafford et al, 2001;Diaz et al, 2004) and the relevant governing rules are debated (Marks, 2003;Bers et al, 2003). The SR Ca 2+ influx is primarily due to the SR/endoplasmic reticulum (ER) Ca 2+ -ATPase (SERCA), a protein found widely in both SR and ER.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Ca2+ leak paradox and “rogue ryanodine receptors”: SR Ca2+ efflux theory and practice

Sobie

Guatimosim

Gómez-Víquez

et al. 2006

Progress in Biophysics and Molecular Biology

115

126

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Ca 2+ efflux from the sarcoplasmic reticulum (SR) is routed primarily through SR Ca 2+ release channels (ryanodine receptors, RyRs). When clusters of RyRs are activated by trigger Ca 2+ influx through L-type Ca 2+ channels (dihydropyridine receptors, DHPR), Ca 2+ sparks are observed. Close spatial coupling between DHPRs and RyR clusters and the relative insensitivity of RyRs to be triggered by Ca 2+ together ensure the stability of this positive-feedback system of Ca 2+ amplification. Despite evidence from single channel RyR gating experiments that phosphorylation of RyRs by protein kinase A (PKA) or calcium-calmodulin dependent protein kinase II (CAMK II) causes an increase in the sensitivity of the RyR to be triggered by [Ca 2+ ] i there is little clear evidence to date showing an increase in Ca 2+ spark rate. Indeed, there is some evidence that the SR Ca 2+ content may be decreased in hyperadrenergic disease states. The question is whether or not these observations are compatible with each other and with the development of arrhythmogenic extrasystoles that can occur under these conditions. Furthermore, the appearance of an increase in the SR Ca 2+ "leak" under these conditions is perplexing. These and related complexities are analyzed and discussed in this report. Using simple mathematical modeling discussed in the context of recent experimental findings, a possible resolution to this paradox is proposed. The resolution depends upon two features of SR function that have not been confirmed directly but are broadly consistent with several lines of indirect evidence: (1) the existence of unclustered or "rogue" RyRs that may respond differently to local [Ca 2+ ] i in diastole and during the [Ca 2+ ] i transient; and (2) a decrease in cooperative or coupled gating between clustered RyRs in response to physiologic phosphorylation or hyperphosphorylation of RyRs in disease states such as heart failure. Taken together, these two features may provide a framework that allows for an improved understanding of cardiac Ca 2+ signaling.

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“…The molecular mechanisms behind this reduction of diastolic cardiac muscle fluctuation were not revealed by the present study. Considering the important role of RyR function in SL fluctuation, the effect of Celacade on SL fluctuation in MI trabeculas might involve a regulatory step of the RyR functional pathway, possibly including RyR phosphorylation by either protein kinase A or Ca 2+ -calmodulin-dependent protein kinase II (2,(15)(16)(17), or alteration of stoichiometry of the FK506 binding protein 12.6 to the channel (18), and increased oxidative stress in the MI heart (19).…”

Section: Effects Of Celacade On Sl Fluctuationsmentioning

confidence: 99%