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(Circulation Research. 2007;100:5.)
© 2007 American Heart Association, Inc.

Editorials

The Cardiac Sarcoplasmic Reticulum

Filled With Ca²⁺ and Surprises

Ernst Niggli

From the Department of Physiology, University of Bern, Switzerland.

Correspondence to Ernst Niggli, Department of Physiology, University of Bern, Bühlplatz 5, CH-3012 Bern, Switzerland. E-mail niggli{at}pyl.unibe.ch

Key Words: Ca²⁺ transients • calcium signaling • ryanodine receptor • sarcoplasmic reticulum

Ca²⁺-induced Ca²⁺ release (CICR) from the sarcoplasmic reticulum (SR) is the cornerstone of cardiac excitation-contraction coupling and Ca²⁺ signaling.^1,2 However, as an amplification mechanism exhibiting a high degree of positive feed-back, it has to be kept in check by inhibitory systems to prevent spontaneous oscillatory Ca²⁺ releases which could possibly trigger cardiac arrhythmias. Local control theory provides us with an initial frame-work to understand how this could be accomplished.³ Mutually independent Ca²⁺ signaling events (Ca²⁺ sparks⁴) generate the necessary amplification locally without spreading to neighboring Ca²⁺ release sites, whereas the normal signal transduction from L-type Ca²⁺ channels to the SR occurs within the microdomain of the dyadic cleft, well isolated from the bulk of the cytosol. Uncoupling between neighboring Ca²⁺ spark sites thus ensures the reliability of the CICR system and occurs by virtue of steep concentration gradients away from the microdomain of Ca²⁺ release, and by means of the relative insensitivity of the SR Ca²⁺ release channels (ryanodine receptors [RyRs]) toward cytosolic Ca²⁺ triggers.⁵ This uncoupling by local control also underlies the observation that Ca²⁺ sparks occurring spontaneously remain localized and do not initiate a chain reaction of Ca²⁺ sparks traveling along the entire myocyte as a Ca²⁺ wave.

However, this system can also become unstable and CICR is capable to override local control and to trigger oscillatory Ca²⁺ signals in cardiomyocytes, particularly under pathophysiological conditions. Waves of contractions traveling along isolated cardiomyocytes have been discovered and the underlying Ca²⁺ waves have been imaged with fluorescent Ca²⁺ indicators quite some time ago.⁶ In principle, local control could fail to confine accidental Ca²⁺ release events because of at least two fundamental reasons: 1) the amount of Ca²⁺ released from the store during a spontaneous Ca²⁺ spark could increase to such an extent that it would be sufficient to trigger CICR from neighboring Ca²⁺ spark sites despite the local control mechanisms, thus initiating a Ca²⁺ wave propagating in a saltatoric fashion along the cell; and 2) the sensitivity of the RyRs toward cytosolic Ca²⁺ triggers could increase to an extent where even the small elevation of cytosolic [Ca²⁺]_i reaching out from a spark becomes sufficient to initiate CICR in neighboring sarcomeres 2 µm away. Although elevated SR Ca²⁺ content during Ca²⁺ overload will lead to more Ca²⁺ being released during a Ca²⁺ spark (by law of mass action), there is recent evidence that the situation may be much more complex. It is more and more recognized that the SR Ca²⁺ concentration can also affect the gating and Ca²⁺ sensitivity of the RyRs, by making the RyRs less Ca²⁺ sensitive on store emptying,⁷ and more sensitive during refilling.⁸ This backward signal may be communicated from the SR lumen to the RyRs after Ca²⁺ binding to calsequestrin (CSQ) and by means of allosteric interactions also involving the two small SR proteins junctin and triadin. Thus, any elevation of the SR Ca²⁺ concentration would inevitably affect both features of the local control system, the diffusional dissipation of the released Ca²⁺ and the Ca²⁺ sensitivity of the RyRs. Furthermore, most conditions leading to arrhythmias because of spontaneous SR Ca²⁺ release are also associated with Ca²⁺ overload (eg, intoxication with cardiac glycosides, ischemia/reperfusion injury). Therefore, it is difficult to separate the two mechanisms contributing to local control and to examine the two possibilities independently of each other in experiments.

However, there are a few notable exceptions, such as the recently discovered mutations in the RyR⁹ (and CSQ¹⁰) proteins, where gating changes could indeed occur separate from and independent of SR Ca²⁺ overload. To understand the pathophysiological consequences of these mutations it is very important to ascertain that the changes of the RyR gating induced by the mutations are per se sufficient to trigger arrhythmias, or whether SR Ca²⁺ overload is required as well. Interestingly, these patients typically develop arrhythmias (catecholaminergic polymorphic ventricular tachycardia [CPVT]) during physical exercise or stress, which may increase RyR open probability further via SR Ca²⁺ loading or RyR phosphorylation.⁹ Thus, from the clinical and experimental manifestations of these channelopathies and CSQ protein mutations described above we cannot conclude whether alterations of RyR gating alone are sufficient to trigger spontaneous Ca²⁺ waves causing arrhythmias.

In the current issue of Circulation Research, Venetucci et al¹¹ present remarkable results obtained from experiments precisely addressing this crucial question. Can isolated changes of RyR gating, for example in the presence of RyR mutations or hyperphosphorylation, initiate and sustain oscillatory and arrhythmogenic SR Ca²⁺ releases or is SR Ca²⁺ overload required as well? As an experimental approach, they used isolated rat ventricular cells and applied a low concentration of caffeine, which is known to sensitize the RyRs for cytosolic Ca²⁺. Their findings clearly indicate that sensitization of RyR by a low concentration of caffeine is not sufficient to elicit Ca²⁺ waves over a longer period of time. This appears to be, at least in part, because of a downstream consequence of the additional RyR activation by caffeine. This additional RyR activation constitutes an enhanced SR Ca²⁺ leak which subsequently leads to a reduction of SR Ca²⁺ load. The reduced SR Ca²⁺ load may in turn result in less Ca²⁺ being released during each spontaneous spark, and may also desensitize the RyRs. Thus, the secondary changes in SR Ca²⁺ content restabilize the system and lead to a new stable state. However, when SR Ca²⁺ content was elevated by application of isoproterenol (ISO), to stimulate the SR Ca²⁺ pump (SERCA2a) by phosphorylation of phospholamban, the myocytes continued to generate Ca²⁺ waves as a consequence of the sustained enhanced RyR Ca²⁺ sensitivity.

Taken together, it appears that one aspect of the local-control mechanism is quite clear: isolated changes of RyR sensitivity to Ca²⁺ (as mediated by caffeine) are not sufficient to sustain prolonged spontaneous CICR activity. Additional elements that depend on SR Ca²⁺ load (and possibly ß-adrenergic stimulation) are required. However, the implications of changed SR Ca²⁺ load are not as clear, in part because elevated luminal SR Ca²⁺ will not only increase CICR by law of mass action, but is also thought to further sensitize the RyRs by the allosteric interactions mentioned above.

Based on these observations one can also see the well established finding of a reduced SR content under conditions of congestive heart failure from a different perspective. Reduced SR content is generally assumed to cause impaired cardiac function and to occur because of reduced SERCA2a expression, possibly further accentuated by an enhanced SR Ca²⁺ leak via hyperphosphorylated RyRs.¹² In the light of the present findings, the low SR Ca²⁺ content might actually reflect a beneficial and adaptive change of Ca²⁺ signaling, to reduce the risk for arrhythmias caused by sensitized RyRs. Thus, the therapeutic strategy to increase the SR Ca²⁺ load in these patients with pharmacological tools or gene therapy approaches to stimulate the SERCA2a may bear a certain risk, particularly when the SR Ca²⁺ load increases too much.¹³ Specifically targeting the RyRs to reduce the SR Ca²⁺ leak may represent a promising alternative which is unlikely to cause Ca²⁺ overload by itself.¹⁴

	Acknowledgments

 
Sources of Funding

Funding was received from Swiss National Science Foundation (SNF 109693.05), Swiss Foundation for Research on Muscle Diseases (SSEM), the Swiss Cardiovascular Research and Training Network (SCRTN), the Swiss State Secretariat for Education and Research (SER) and the European Commission (RTN2–2001-00337).

Disclosures

None.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

Top References

 

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