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Ca²⁺ Sparks in Cardiac Muscle: Is There Life Without Them?

Ernst Niggli

E. Niggli is in the Department of Physiology, University of Bern, 3012 Bern, Switzerland (E-mail: niggli{at}pyl.unibe.ch; http://beam.to/calcium_quark).

	Abstract

 
The discovery of elementary Ca²⁺ signaling events, the Ca²⁺ sparks, has profoundly changed our view of cardiac Ca²⁺ signaling and, in particular, excitationcontraction coupling. In addition, a partial disruption of cardiac Ca²⁺ signaling may be important in clinical cardiac conditions such as congestive heart failure. Understanding cardiac diseases on the cellular and molecular levels may provide a key to new pharmacological strategies in the near future.

	Introduction

Top Introduction The paradox of cardiac... Are these experimental results... Local control theories offer... The Ca2+ spark as... Ca2+ signaling is affected... Impaired EC coupling may... Are there other safety... Na+ current-induced Ca2+ release... T-type Ca2+ current and... Ca2+ release activated by... EC coupling may be... References

 
In heart muscle, the process of excitation-contraction (EC) coupling is of vital importance because it links the electrical excitation to the mechanical activity of cardiac muscle cells. Would it be reasonable to assume that this crucial process underlies some physiological regulation or that it is affected by certain pathological cardiac conditions? If this question had been presented to an expert in the field only a few years ago, the answer would almost inevitably have been "No!" Why expect such a dogmatic response? Cardiac EC coupling is known to be initiated by Ca²⁺ influx into cardiac myocytes via voltage-dependent L-type Ca²⁺ channels (i.e., dihydropyridine receptors, DHPRs) that are activated during each action potential (see Fig. 1). This initial signal acts only as a trigger for subsequent Ca²⁺-induced Ca²⁺ release (CICR) from intracellular Ca²⁺ stores in the sarcoplasmic reticulum (SR). This secondary Ca²⁺ release occurs via large homotetrameric Ca²⁺-release channels (i.e., the ryanodine receptors, RyRs), located in the membrane of the SR. In most mammalian species, CICR amplifies the initial trigger signal severalfold. Because this amplification system functions reliably during billions of heartbeats over several decades (in human hearts), the chances for CICR to fail must be exceedingly small. In fact, should it fail, the heart would immediately stop beating. Therefore, it seems unlikely that nature would tinker with such a vital system and dare to regulate it. The purpose of this review is to outline how and why the answer to the question posed above has fundamentally changed during the last few years.

View larger version (27K): [in this window] [in a new window]   FIGURE 1. Schematic diagram of a cardiac myocyte and the most important elements of Ca2+ signaling and excitation-contraction (EC) coupling. DHPR, dihydropyridine receptor; RyR, ryanodine receptor; SR, sarcoplasmic reticulum. For details see text.

	The paradox of cardiac Ca2+ signaling

Top Introduction The paradox of cardiac... Are these experimental results... Local control theories offer... The Ca2+ spark as... Ca2+ signaling is affected... Impaired EC coupling may... Are there other safety... Na+ current-induced Ca2+ release... T-type Ca2+ current and... Ca2+ release activated by... EC coupling may be... References

However, a few years ago several disturbing and incompatible experimental observations were reported that did not appear to fit into this picture. First of all, it was clearly shown by several research laboratories that Ca²⁺ release from the SR was not necessarily all-or-none. In contrast, it was found that small or abbreviated L-type Ca²⁺ currents could elicit smaller than usual SR Ca²⁺ release, indicating that CICR remains under the control of the trigger signal (i.e., the L-type Ca²⁺ current) and does not become self-sustaining. This finding was clearly inconsistent with the hitherto assumed all-or-none behavior. Another line of evidence challenging the all-or-none concept could be derived from Ca²⁺ signaling and imaging experiments that were designed to generate a subcellularly localized Ca²⁺ signal in single myocytes. This was accomplished either by superfusing only one end of the isolated cell with a Ca²⁺-containing solution or with photochemical techniques (14). These studies showed that experimentally induced Ca²⁺ waves only propagate in cells that are overloaded with Ca²⁺, whereas in normal cells, localized Ca²⁺ release remains local, again suggesting that CICR usually does not operate under an all-or-none regime. These findings, apparently in conflict with those outlined above, led to the recognition of the "paradox of cardiac Ca²⁺ signaling," raising the following question: How could the observed amplification of the inherently self-sustaining CICR be achieved while still maintaining perfect control over SR Ca²⁺ release?

	Are these experimental results physiologically relevant?

Top Introduction The paradox of cardiac... Are these experimental results... Local control theories offer... The Ca2+ spark as... Ca2+ signaling is affected... Impaired EC coupling may... Are there other safety... Na+ current-induced Ca2+ release... T-type Ca2+ current and... Ca2+ release activated by... EC coupling may be... References

 
All findings suggesting maintained control of CICR by the trigger signal were obtained under highly artificial experimental conditions. Neither abbreviated nor small depolarizations occur in vivo, where the action potential ensures a reasonable depolarization to a well-defined potential and with a sufficient duration. There is also no possibility for one end of a myocyte alone to be exposed to low extracellular Ca²⁺. Could these experimental observations thus be regarded as curiosities with limited or no physiological relevance? Certainly not! First of all, any comprehensive model of cardiac Ca²⁺ signaling and EC coupling should be able to explain and reproduce all experimental findings, no matter under what conditions they were obtained. Secondly, if simple experimental interventions can impair or alter EC coupling in unexpected ways, it can certainly not be excluded a priori that some cardiac diseases could cause a similar deficiency.

	Local control theories offer solution for this paradox

Top Introduction The paradox of cardiac... Are these experimental results... Local control theories offer... The Ca2+ spark as... Ca2+ signaling is affected... Impaired EC coupling may... Are there other safety... Na+ current-induced Ca2+ release... T-type Ca2+ current and... Ca2+ release activated by... EC coupling may be... References

 
Mathematical simulations of cardiac Ca²⁺ signaling suggested that the observed amplification of CICR was not achievable with a "common pool" model, i.e., a system in which the Ca²⁺ influx via L-type Ca²⁺ channels and the Ca²⁺ release from the SR reach a common pool, the bulk cytosol. It was proposed that, instead, localized domains of very high Ca²⁺ near the site of Ca²⁺ entry and release are functionally important and link individual L-type Ca²⁺ channels to single RyRs (to form a "Ca²⁺ synapse") or to clusters of RyRs (to form a "cluster bomb") (13). This scheme would allow local control of RyRs by virtue of the highly localized domain of elevated [Ca²⁺]_i. Each of these functional units could exhibit a very high amplification (i.e., behave as an all-or-none system), while the mutual independence of these units would prevent spreading of the Ca²⁺ release signal across the entire cell. Recruiting fewer or more functional release units would thus allow SR Ca²⁺ release to be quantitatively graded with the L-type Ca²⁺ current.

	The Ca2+ spark as the functional unit of Ca2+ signaling

Top Introduction The paradox of cardiac... Are these experimental results... Local control theories offer... The Ca2+ spark as... Ca2+ signaling is affected... Impaired EC coupling may... Are there other safety... Na+ current-induced Ca2+ release... T-type Ca2+ current and... Ca2+ release activated by... EC coupling may be... References

 
An experimental equivalent of this proposed localized Ca²⁺ domain—the Ca²⁺ spark—was indeed observed when laser scanning confocal microscopy and fluorescent Ca²⁺ indicators were used to image subcellular Ca²⁺ signals (1). Ca²⁺ sparks are characterized by a short duration ( 50 ms) and by a limited spatial spread ( 1.5 µm). Both the time course and the spatial spread are most likely governed by diffusion of Ca²⁺ away from the point source of release. Opening of a single L-type Ca²⁺ channel appears to be sufficient to fire a Ca²⁺ spark from one or several RyRs located in close proximity in the dyadic cleft (Ref. 9 Fig. 2). Each Ca²⁺ spark corresponds to a probabilistic event that is either triggered or not triggered (i.e., an all-or-none event). The probability for the activation of a Ca²⁺ spark is known to depend on, among other factors, the amount of Ca²⁺ entering the dyadic cleft during the L-type Ca²⁺ channel opening. Note that in healthy cardiac myocytes the Ca²⁺ released during a single Ca²⁺ spark does not trigger more distant Ca²⁺ release units. This functional independence from neighboring Ca²⁺ release sites allows the successive recruitment of such release units by the opening of fewer or more L-type Ca²⁺ channels to form an overall Ca²⁺ transient in a controlled and graded fashion.

View larger version (43K): [in this window] [in a new window]   FIGURE 2. Possible sequence of events that may occur in the dyadic cleft during a Ca2+ spark. At time = 1 ms, an L-type Ca2+ channel (DHPR) opens and elevates cytosolic Ca2+ concentration ([Ca2+]i) in a domain around its inner pore. At 2 ms, the RyR immediately facing the active DHPR has also started to release Ca2+ and [Ca2+]i is elevated in the entire dyad. This may trigger additional Ca2+ release from other RyRs located in the immediate vicinity (5 ms). The sum of the individual Ca2+ release events would then form a Ca2+ spark.

	Ca2+ signaling is affected in various cardiac disease models

Top Introduction The paradox of cardiac... Are these experimental results... Local control theories offer... The Ca2+ spark as... Ca2+ signaling is affected... Impaired EC coupling may... Are there other safety... Na+ current-induced Ca2+ release... T-type Ca2+ current and... Ca2+ release activated by... EC coupling may be... References

 
Cardiac force may decline because of a modification of the Ca²⁺ sensitivity of the myofilaments, a deterioration of the Ca²⁺ signals, or both. Disease-related changes of Ca²⁺ signaling in heart muscle have been investigated in several laboratories. Numerous studies have been conducted in a variety of preparations and animal disease models and also in human tissue and isolated myocytes (3). In general, the literature is highly controversial, possibly as a result of peculiarities in the disease models used. In addition, it is frequently not yet clear whether the observed changes of cardiac Ca²⁺ signaling are pathogenic to a particular disease or an adaptive consequence of the deteriorated cardiac function. Nevertheless, the following general picture has emerged. During many cardiac conditions, including hypertrophy and failure, several Ca²⁺ signaling pathways are affected. In the majority of studies on failing hearts, resting [Ca²⁺]_i was found to be slightly elevated whereas the Ca²⁺ transients were reduced in amplitude and exhibited a slowed relaxation. In particular, the function of the SR Ca²⁺ pump and the Na⁺/Ca²⁺ exchanger was found to be altered to varying degrees, with the SR Ca²⁺ pump frequently exhibiting a diminished expression. In some studies, but not all, the observed changes in the expression of the protein or mRNA were paralleled by alterations of transport function. In other studies, changes of Ca²⁺ signaling appeared to result from a functional modification of a particular transporter and not from a change in the amount of expressed protein. In summary, more work must be carried out for full understanding of the pathophysiology of Ca²⁺ signaling during various cardiac diseases, including hypertrophy and failure.

	Impaired EC coupling may be relevant for cardiac failure

Top Introduction The paradox of cardiac... Are these experimental results... Local control theories offer... The Ca2+ spark as... Ca2+ signaling is affected... Impaired EC coupling may... Are there other safety... Na+ current-induced Ca2+ release... T-type Ca2+ current and... Ca2+ release activated by... EC coupling may be... References

 
Safety and reliability were considered to be the most salient features of EC coupling, and there appeared to be little room for regulation or modulation of this vital signaling step, as outlined above. Thus cardiac dysfunction was believed to arise primarily from disturbances taking place either before or after EC coupling itself (for example, a reduction of the Ca²⁺ current or an impaired SR Ca²⁺ buffering causing less release and slowed Ca²⁺ reuptake). Because this view prevailed until recently, it came as a surprise when experiments performed in cardiac myocytes isolated from spontaneously hypertensive rats with heart failure suggested that EC coupling itself may indeed be affected. When the probability of L-type Ca²⁺ channel openings to trigger SR Ca²⁺ release via RyRs was examined, it was found that hypertrophied as well as failing hearts showed a decreased EC coupling efficiency (2). However, both the L-type Ca²⁺ current and the SR Ca²⁺-release mechanism itself appeared to be unaffected by the disease and were normal. These observations were interpreted to indicate that the problem may reside in the link between the two Ca²⁺ signaling proteins, the DHPRs and the RyRs. This view was supported by the observation that increasing the Ca²⁺ influx via the L-type Ca²⁺ current by ß-adrenergic stimulation restored the coupling process to normal in hypertrophied cells (but not in cells isolated from failing hearts). ß-Adrenergic stimulation can prolong the open time of the L-type Ca²⁺ channels and therefore increase the amount of Ca²⁺ entering during a given single channel opening. How could ß-adrenergic stimulation thereby restore the failing Ca²⁺ signaling link? As an attractive hypothesis, it has been proposed that the impaired EC coupling may result from a disarrangement in the microarchitecture of the abutting DHPRs and RyRs. In other words, the juxtaposition of DHPRs and RyRs may have become disrupted or the volume into which Ca²⁺ is distributing within the dyadic cleft may have increased (2). Although this is an intriguing possibility, to date no direct evidence for this hypothesis is available and other mechanisms are also conceivable. For example, the Ca²⁺ sensitivity of the RyRs may have decreased as a direct or indirect consequence of the disease. ß-Adrenergic stimulation could then restore normal Ca²⁺ sensitivity, possibly via phosphorylation of the RyRs. In addition, increased influx of Ca²⁺ during L-type Ca²⁺ current would raise the SR Ca²⁺ load and produce a more maintained augmentation of the Ca²⁺ signal.

In another study performed in rats, arterial hypertension was induced by introducing a constriction of the abdominal aorta ("banding"; Ref. 10). In these animals, the EC coupling efficacy appeared unaltered when the isolated cells were bathed in normal superfusion solution, but reducing the extracellular Ca²⁺ concentration ([Ca²⁺]_o) unmasked a subtle deterioration of the EC coupling process. Reducing [Ca²⁺]_o is expected to lower the Ca²⁺ influx during each opening of an L-type Ca²⁺ channel and may thus lead to failure in the generation of Ca²⁺ sparks if the margin of safety for EC coupling is reduced. In a sense, this experimental intervention represents the opposite of enhancing Ca²⁺ influx during each channel opening by ß-adrenergic stimulation.

In summary, cardiac diseases appear to exist that can seriously interfere with the efficacy and reliability of the EC coupling process. Improving the performance of this crucial process may offer a new avenue to pharmacological treatment of cardiac hypertrophy and failure.

	Are there other safety mechanisms to ensure reliable EC coupling?

Top Introduction The paradox of cardiac... Are these experimental results... Local control theories offer... The Ca2+ spark as... Ca2+ signaling is affected... Impaired EC coupling may... Are there other safety... Na+ current-induced Ca2+ release... T-type Ca2+ current and... Ca2+ release activated by... EC coupling may be... References

 
It is also important to note that disturbances of EC coupling may have a tendency to be self-limiting or even transient, because, as the Ca²⁺ release from the SR is reduced, the SR Ca²⁺ load increases gradually and this would compensate for the reduced trigger efficiency. From the beneficial effect of ß-adrenergic stimulation it can be concluded that compensatory mechanisms during cardiac hypertrophy may be able to maintain sufficient EC coupling despite some problems in the EC coupling machinery. In addition to the compensatory increase of L-type Ca²⁺ flux, other safety mechanisms may work in parallel. Some of these mechanisms could be functioning continuously, whereas others might only become activated when the heart starts to fail. It is conceivable that such parallel mechanisms may boost EC coupling and provide additional safety that guarantees reliable coupling. Indeed, during the last few years several mechanisms have been proposed to work in parallel with the L-type Ca²⁺ current. However, the observations underlying these suggestions were made under highly artificial experimental conditions. Thus their relevance during normal Ca²⁺ signaling is not known at present. Although such redundant mechanisms may not be important normally, they may become essential in pathological conditions. As a starting point, it seems appropriate to consider such auxiliary mechanisms as possible safety nets.

Most proposed supplementary coupling schemes imply a pathway for transsarcolemmal Ca²⁺ entry different from L-type Ca²⁺ current that may be activated during the action potential. With a few exceptions, the existence of these pathways is fairly well established and they are known to be able to carry Ca²⁺ into cardiac myocytes. However, the Ca²⁺ flux normally mediated by each of these mechanisms was not generally thought to be sufficient to account for significant Ca²⁺ release from the SR.

	Na+ current-induced Ca2+ release and Na+/Ca2+ exchange activation by depolarization

Top Introduction The paradox of cardiac... Are these experimental results... Local control theories offer... The Ca2+ spark as... Ca2+ signaling is affected... Impaired EC coupling may... Are there other safety... Na+ current-induced Ca2+ release... T-type Ca2+ current and... Ca2+ release activated by... EC coupling may be... References

 
Several years ago Leblanc and Hume (6) reported the surprising observation that Na⁺ current (I_Na) was able to trigger Ca²⁺ release from the SR in isolated guinea pig ventricular myocytes. Because this type of Ca²⁺ release was dependent on the presence of extracellular Ca²⁺ but was insensitive to blockers of L-type Ca²⁺ channels, it was proposed that the subsarcolemmal Na⁺ accumulation during I_Na may be sufficient to activate the Na⁺/Ca²⁺ exchange in the Ca²⁺ influx mode. Ca²⁺ entry via Na⁺/Ca²⁺ exchange would subsequently trigger SR Ca²⁺ release by CICR. This pathway for the activation of CICR had been overlooked for many years because in most voltage-clamp studies I_Na was either blocked by tetrodotoxin (TTX) or inactivated by depolarization to prevent loss of voltage control. The relevance of this parallel pathway for Ca²⁺ entry and the interpretation of the data are still discussed because several laboratories could not reproduce these results. A confocal microscopic study of I_Na-induced Ca²⁺ release revealed that this type of Ca²⁺ signal was spatially homogeneous (i.e.,comprised no Ca²⁺ sparks; Ref. 7). The significance of this observation is not yet clear, but it may be related to other observations of homogeneous SR Ca²⁺ release in cardiac myocytes. When Ca²⁺ was photoreleased from caged compounds, spatially uniform Ca²⁺ release was also observed and the existence of a functional SR Ca²⁺ release unit smaller than a Ca²⁺ spark—the Ca²⁺ quark—was proposed to explain these observations (8). This would support the notion that I_Na-induced SR Ca²⁺ release occurs via a pathway that is fundamentally different from L-type Ca²⁺ channels, which would trigger Ca²⁺ sparks.

The Na⁺/Ca²⁺ exchange has a reversal potential that depends on the electrochemical gradients for both Ca²⁺ and Na⁺. At rest, this reversal potential is around –40 mV. A depolarization of the cell membrane beyond the reversal potential is expected to activate Ca²⁺ influx via Na⁺/Ca²⁺ exchange, for example, early during the action potential, immediately before [Ca²⁺]_i starts to rise. Later during the action potential, the elevation of [Ca²⁺]_i shifts the reversal potential of the Na⁺/Ca²⁺ exchange to more positive potentials and the Na⁺/Ca²⁺ exchange starts to remove Ca²⁺ from the cytosol. In some studies, depolarization of the cell membrane alone was indeed observed to generate Ca²⁺ influx via Na⁺/Ca²⁺ exchange sufficient for triggering SR Ca²⁺ release (5). Again, although the mechanism is known to work in principle, the relevance of this Ca²⁺ influx pathway under physiological conditions is unclear. However, voltage-dependent changes of the Na⁺/Ca²⁺ exchanger could work synergistically with the subsarcolemmal accumulation of Na⁺ during I_Na (see above).

	T-type Ca2+ current and slip-mode Ca2+ conductance of Na+ channels

Top Introduction The paradox of cardiac... Are these experimental results... Local control theories offer... The Ca2+ spark as... Ca2+ signaling is affected... Impaired EC coupling may... Are there other safety... Na+ current-induced Ca2+ release... T-type Ca2+ current and... Ca2+ release activated by... EC coupling may be... References

 
Many mammalian cardiac myocytes contain T-type Ca²⁺ channels, in addition to the L type. Compared to the latter, T-type channels activate and inactivate at more negative membrane potentials. Therefore, their contribution may also have been overlooked in experiments in which cells were predepolarized to inactivate I_Na. In a recent study that was designed to investigate a possible role of the T-type Ca²⁺ current during EC coupling, a small contribution of these Ca²⁺ channels was suspected (12), but the coupling efficacy appeared to be smaller than for the L-type channels.

Earlier, cardiac TTX-sensitive Na⁺ channels were suspected to carry Ca²⁺ but only noticeably when the extracellular Na⁺ concentration was very low. Surprisingly, a recent report suggested that after ß-adrenergic stimulation, the Na⁺ selectivity of the TTX-sensitive Na⁺ channels dramatically diminishes, allowing significant Ca²⁺ influx during I_Na (11). In fact, the permeability ratio for Na⁺ to Ca²⁺ was determined to be 1:1.25 after ß-adrenergic stimulation, and the Ca²⁺ influx was found to be sufficient to trigger SR Ca²⁺ release on its own. Therefore, I_Na may kick in as an auxiliary pathway for Ca²⁺ entry into cardiac myocytes under conditions of ß-adrenergic stimulation.

	Ca2+ release activated by voltage or by inositol 1,4,5-trisphosphate

Top Introduction The paradox of cardiac... Are these experimental results... Local control theories offer... The Ca2+ spark as... Ca2+ signaling is affected... Impaired EC coupling may... Are there other safety... Na+ current-induced Ca2+ release... T-type Ca2+ current and... Ca2+ release activated by... EC coupling may be... References

 
SR Ca²⁺ release in skeletal muscle does not require influx of Ca²⁺. Instead, voltage sensors are thought to be directly linked with the RyRs. Because of the ultrastructural similarities between cardiac and skeletal muscle, a functional analogy has long been suspected. Indeed, several reports have appeared suggesting a voltage-sensitive release mechanism (VSRM) or voltage-activated Ca²⁺ release (VACR) (4). Interestingly, this mechanism also needs elevated levels of cAMP or ß-adrenergic stimulation, like the slip mode of I_Na. Because cardiac muscle cells contain a variety of routes for Ca²⁺ entry, it is very challenging to rigorously show that VSRM (or VACR) does not require Ca²⁺ entry. This is particularly difficult because the mechanism seems to require the presence of extracellular Ca²⁺ and because the pharmacological tools that block the various Ca²⁺ entry pathways are far from perfect.

Many nonexcitable cells use Ca²⁺ release from intracellular stores for signaling. In these cells, the second messenger is inositol 1,4,5-trisphosphate (IP₃) and the Ca²⁺-release channel is the IP₃ receptor (IP₃R) with many structural and functional similarities to the RyRs. Because IP₃Rs were also detected in cardiac muscle, several studies investigated the role of IP₃ in cardiac EC coupling. The present view is that, in cardiac muscle, IP₃ only generates small Ca²⁺ release signals that are also too slow to participate in rapid EC coupling events. However, this signaling system could play a modulatory or compensatory role during some cardiac diseases.

	EC coupling may be clinically relevant

Top Introduction The paradox of cardiac... Are these experimental results... Local control theories offer... The Ca2+ spark as... Ca2+ signaling is affected... Impaired EC coupling may... Are there other safety... Na+ current-induced Ca2+ release... T-type Ca2+ current and... Ca2+ release activated by... EC coupling may be... References

 
The discovery of elementary events for Ca²⁺ signaling was helpful for solving a paradox in cardiac Ca²⁺ signaling. Together with several potential auxiliary pathways for cardiac Ca²⁺ signaling, Ca²⁺ sparks also allow for a partial failure of EC coupling without catastrophic consequences. Sorting out the precise contribution of each EC coupling pathway in normal and pathological conditions will be difficult and will require much more work because of the complexity of cardiac Ca²⁺ signaling. Therefore, the answer to the question posed in the title of the present review is not straightforward. The heart seems to be able to cope with a reduced efficiency of Ca²⁺ spark generation, but at present we do not yet know to what extent other Ca²⁺ signaling pathways can compensate for a partial failure of the L-type Ca²⁺ current as the main trigger. However, as we untangle this complex system in the future, we may be able to conceptualize completely new pharmacological strategies. It is also pleasing that this notable opportunity directly illustrates the potential and benefit of basic research. Even if the "value" of this research is not immediate in terms of financial profit, it is impossible to predict, by both scientists and politicians, whether an apparently small piece of the puzzle may become pivotal for the big picture at some time in the future. Taken together, these results suggest that EC coupling may be more important than previously thought for both cardiac physiology and pathophysiology.

	Acknowledgments

 
I would like to thank Drs. H. P. Clamann and F. DelPrincipe for critical reading of the manuscript and Dr. H. R. Lüscher for his valuable suggestions. Financial support was provided by the Swiss National Science Foundation (Grant 31-50564.97).

	References

Top Introduction The paradox of cardiac... Are these experimental results... Local control theories offer... The Ca2+ spark as... Ca2+ signaling is affected... Impaired EC coupling may... Are there other safety... Na+ current-induced Ca2+ release... T-type Ca2+ current and... Ca2+ release activated by... EC coupling may be... References

 

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