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Circulation Research. 1999;85:770-776

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Right arrow Calcium cycling/excitation-contraction coupling
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(Circulation Research. 1999;85:770-776.)
© 1999 American Heart Association, Inc.


Reviews

Ca2+ Release Mechanisms, Ca2+ Sparks, and Local Control of Excitation-Contraction Coupling in Normal Heart Muscle

Withrow Gil Wier, C. William Balke

From the Departments of Physiology and Medicine, School of Medicine, University of Maryland, 655 W Baltimore St, Baltimore, MD, 21201.

Correspondence to Dr W. Gil Wier, Department of Physiology, University of Maryland, Baltimore, 655 W Baltimore St, Baltimore, MD 21201. E-mail gwier001{at}umaryland.edu


Key Words: Ca2+ spark • excitation-contraction coupling • L-type Ca2+ channel • sarcoplasmic reticulum • ryanodine receptor


*    Introduction
up arrowTop
*Introduction
down arrow"Local Control" Theory of...
down arrowVisualization of Local SR...
down arrowOther Putative Sources of...
down arrowPutative Protein Kinase A...
down arrowSummary
down arrowReferences
 
It is well established that most of the Ca2+ that activates contraction in mammalian heart is released from the sarcoplasmic reticulum (SR) through ryanodine receptors (RyR) and that the RyR are themselves activated by Ca2+ in the mechanism known as "Ca2+ induced Ca2+ release" (CICR).1 Confocal imaging has made possible the visualization of localized Ca2+ release through RyR, in the form of Ca2+ sparks.2 It appears that Ca2+ sparks are triggered by a local [Ca2+]i,, which is different from the spatial average [Ca2+]i, and which is established first in the region of the RyR by the opening of a single L-type Ca2+ channel.3 4 These phenomena are the basis of the theory of excitation-contraction (E-C) coupling known as "local control," which was predicted so presciently by Michael D. Stern in 1992.5 Nevertheless, the molecular mechanisms of Ca2+ sparks and the nature of the triggering by Ca2+ entry are still obscure. To complicate matters further, other possible sources of Ca2+ that activate, or "trigger," this release have been proposed recently, and it has even been suggested that a voltage-sensitive release mechanism, which does not require Ca2+, may exist in cardiac muscle, similar to that in skeletal muscle.6 It is our intention here to review the evidence for local control of E-C coupling in normal heart muscle and to evaluate critically the evidence for additional sources of trigger Ca2+ or mechanisms of SR Ca2+ release. We emphasize, however, that concepts about cardiac Ca2+ sparks, and their possible role in cardiac E-C coupling, do not necessarily extend to Ca2+ sparks that occur in smooth muscle and skeletal muscle. Local Ca2+ release in smooth muscle cells has also been called Ca2+ sparks,7 but is thought to modulate relaxation,8 rather than contraction. Local release events similar to Ca2+ sparks are not observed in adult mammalian skeletal muscle at all during E-C coupling.9


*    "Local Control" Theory of Cardiac E-C Coupling
up arrowTop
up arrowIntroduction
*"Local Control" Theory of...
down arrowVisualization of Local SR...
down arrowOther Putative Sources of...
down arrowPutative Protein Kinase A...
down arrowSummary
down arrowReferences
 
The essence of the "local control" theory of E-C coupling in cardiac muscle is that SR Ca2+ release is controlled by the L-type Ca2+ current because independent, elementary events of SR Ca2+ release are "recruited" by Ca2+ flowing through single L-type Ca2+ channels, and not by the average [Ca2+]i within the cell. One of the structural bases of local control is the separation of SR Ca2+ release channels (RyR) at the ends of sarcomeres, near L-type Ca2+ channels in transverse tubules. There, RyR can be activated strictly by the Ca2+ in their own immediate (local) molecular environment. In local control theory, the [Ca2+] in that environment is established first by Ca2+ entry via L-type Ca2+ channels, and the release in separate clusters of RyR is independent of release in other such clusters, by virtue of physical separation. Such triggered local release appears to be manifest as the so-called Ca2+ "sparks,"2 first observed as spontaneous events of SR Ca2+ release. Although the exact nature and origin of Ca2+ sparks remain uncertain, the prevailing view is that the whole-cell Ca2+ transient may be explained as the spatial and temporal summation of Ca2+ sparks, each triggered locally by the flow of current through a single L-type Ca2+ channel.

Indirect evidence of local control of cardiac SR Ca2+ release was obtained from analysis of the relationship between whole-cell Ca2+ current and whole-cell SR Ca2+ release flux.10 11 Work of the previous years had produced a detailed description and theory of the whole-cell Ca2+ transient, in terms of the various cellular processes determining cytoplasmic free [Ca2+].12 13 14 15 16 Control of SR Ca2+ release by L-type Ca2+ current was established by similarities in the voltage dependence of peak SR Ca2+ release flux and peak Ca2+ current,10 and by the fact that SR Ca2+ release can be turned off by stopping the Ca2+ current rapidly,10 either by repolarization (where current deactivates) or by depolarization to very positive voltages (where driving force for Ca2+ entry is small). SR Ca2+ release can also be triggered by "tails" of Ca2+ current through L-type Ca2+ channels on repolarization from positive pulse potentials.12 (Repolarization would be expected only to deactivate a voltage-dependent release mechanism.) The key observation in suggesting local control, however, was that although both peak SR Ca2+ release and peak L-type Ca2+ current displayed a bell-shaped dependence on membrane voltage during voltage-clamp pulses, the relationships were, in fact, different. Small Ca2+ currents at negative potentials (where single-channel currents are relatively large) were much more efficacious in triggering SR Ca2+ release than Ca2+ currents at positive potentials (where single channel currents are more frequent but smaller). On the basis of these data, we11 postulated that SR Ca2+ release flux was controlled locally, by single L-type Ca2+ channel currents. Local release events could not be resolved, however, with the methods available at that time.


*    Visualization of Local SR Ca2+ Release: Ca2+ Sparks
up arrowTop
up arrowIntroduction
up arrow"Local Control" Theory of...
*Visualization of Local SR...
down arrowOther Putative Sources of...
down arrowPutative Protein Kinase A...
down arrowSummary
down arrowReferences
 
The first observation of local SR Ca2+ release (aside from Ca2+ waves) was that of Cheng et al,2 who used confocal microscopy to see small, spontaneous, nonpropagating fluorescence transients in fluo-3–loaded rat cardiac cells. They named the fluorescent events "Ca2+ sparks." They concluded from the effects of ryanodine that the Ca2+ sparks arose from the SR and represented release of Ca2+ from one or a small group of RyR. It was postulated in that work that such events might also occur with electrical excitation.

Ca2+ Sparks Evoked by Electrical Depolarization: Relation to L-type Ca2+ Current
After the initial report of spontaneous Ca2+ sparks, several studies appeared in which Ca2+ sparks were evoked by electrical stimulation, thus providing the first direct evidence that Ca2+ sparks might underlie SR Ca2+ release during normal E-C coupling. The first study combining whole-cell voltage clamp and confocal microscopy17 revealed local, ryanodine-sensitive, inhomogeneities in Ca2+ during small depolarizing pulses that evoked only small Ca2+ currents. These evoked local transients appeared to be identical to spontaneous Ca2+ sparks, recorded in the same cells. Spatially averaged [Ca2+], obtained by integrating line-scan images, was identical to that obtained in the earlier studies in which whole-cell Ca2+ had been measured. These results made abundantly clear the fact that observations of spatially averaged [Ca2+] would be misleading for the understanding of E-C coupling, given that the spatially averaged [Ca2+] was clearly different from that in the region of the RyR. The sparks occurred near t-tubules.18 Similar results were obtained during action potentials,19 and cadmium, a blocker of L-type Ca2+ channels, increased the inhomogeneity of the Ca2+ transient, suggesting that individual SR release events were distinguishable.

In a detailed study,3 it was shown that Ca2+ sparks were evoked with a time and voltage dependence similar to that expected for first latency histograms of L-type Ca2+ channels.20 When the probability of L-type Ca2+ channel activation is made extremely low through the use of Ca2+ channel blockers, only a few, widely separated L-type Ca2+ channels will open. Changes in spatial average [Ca2+]i were negligibly small under this condition, rendering it unlikely that the Ca2+ sparks could be triggered by anything other than the opening of a nearby L-type Ca2+ channel. Although single-channel currents could not be recorded or localized, it seems reasonable that the only factors that could explain the voltage and time dependence of the spatially isolated sparks were the voltage and time dependence of single L-type Ca2+ channels. A different study at the same time reached the same conclusion by showing that the number of Ca2+ sparks increased with voltage during ramped depolarization (-70 to -40 mV), similarly to the increase of the Ca2+ current with voltage during the ramp.4 Recently, two new studies21 22 have confirmed the original Ca2+ spark latency histograms3 and presented the experimental relationship between Ca2+ currents and Ca2+ spark probability in much more detail.

Several attempts have been made to describe precisely the mathematical relationship between the probability of evoking Ca2+ sparks and the Ca2+ current. The first of these3 provided the basic equation for the probability (Pi) that a Ca2+ spark will be triggered by the opening of a single L-type Ca2+ channel. A subsequent attempt used a similar analysis23 but failed to take into account the time dependence of the probability of L-type Ca2+ channel opening. This problem has now been recognized and clarified.24 The most detailed analysis of experimental data so far has been that of Collier et al,21 who found that the time constants describing Ca2+ current and Ca2+ spark occurrence were not significantly different at membrane potentials between -30 and +30 mV. From comparison of the experimental results to a simple model, these authors were able to confirm that the opening of a single L-type Ca2+ channel initiates a Ca2+ spark. Thus, the body of experimental and theoretical work, to date, supports the idea that Ca2+ sparks are triggered by the opening of a single L-type Ca2+ channel.

The question of how many Ca2+ ions must bind to an RyR to initiate a Ca2+ spark remains controversial. Mathematical modeling of the dyadic space suggested that the local [Ca2+]i would be proportional to the single L-type Ca2+ channel current, i.25 Some data have been presented23 that spark probability is dependent on the square (ie, power, 2) of the single channel current (and, therefore, possibly, on the square of local [Ca2+]) as might arise if two Ca2+ bind to an RyR to trigger a spark. A recent study26 using whole-cell Ca2+ transients and Ca2+ currents, however, demonstrated a linear relationship between peak Ca2+ currents and the maximum rate of rise of the Ca2+ transient, and the results were interpreted to mean that only one Ca2+ need bind to activate an RyR and Ca2+ release. The use of whole-cell fluorescence transients for this calculation seems inherently less reliable a method, as opposed to observing Ca2+ sparks directly.

Finally, activation of Ca2+ sparks by patch depolarization of cardiac cells has been achieved,27 although the probabilities of activation were lower than would be required for normal E-C coupling. It seems likely that formation of the membrane patch recording disrupted the normal coupling between L-type Ca2+ channel and RyR. Thus, direct evidence, in the form of simultaneous recordings, that a single opening of a single L-type Ca2+ channel can trigger a Ca2+ spark, is still lacking.

Ca2+ Sparks Sum in Space and Time to Produce the Whole-Cell Ca2+ Transient
The work described above supported the concept that Ca2+ sparks are activated by L-type Ca2+ channel currents but did not establish directly that Ca2+ sparks summed independently to produce the whole-cell Ca2+ transient. Cannell et al19 had provided theoretical evidence of the feasibility of this idea. The fact that the total number of Ca2+ sparks depended on voltage in the same manner as the whole-cell Ca2+ transient3 also implied that this was true. Nevertheless, direct evidence on this point has been lacking, until recently, when local Ca2+ release has been imaged with fast confocal microscopes with line scanning28 and with 2D (full frame) imaging.22 The line-scan images28 showed local release, at z lines, during the initial phase of a normal Ca2+ transient. Furthermore, if a Ca2+ spark had occurred spontaneously just previously at a particular z line, then release failed at that z line, indicating directly the role of Ca2+ sparks in E-C coupling (and that the processes producing Ca2+ sparks may experience refractoriness). The fast 2D images22 also showed localized release, probably at dyadic junctions. It has been suggested that the nonlinear relationship between single-channel current and SR Ca2+ release (possibly dependent on i2) provides a mechanism whereby relatively small local changes in [Ca2+]i can increase spark probability by a factor of 104 during normal E-C coupling.24

Whole-cell Ca2+ release flux has been measured directly recently29 using a novel fluorescence method, in which cytoplasmic [Ca2+]i is reduced through the use of high concentrations of EGTA, and localized SR Ca2+ release is observed with the low-affinity fast Ca2+ indicator, Oregon Green 488 BAPTA-5N. This method permits visualization of release at specific sites during voltage-clamp pulses. The overall waveform of the release and its absolute value were reported similar to that obtained earlier,10 11 16 through mathematical analysis of the whole-cell Ca2+ transient, in the absence of EGTA. The number of Ca2+ sparks involved in the total release flux remains to be determined.

Molecular Origin and Mechanisms of Cardiac Ca2+ Sparks
The molecule responsible for Ca2+ sparks in cardiac muscle is the RyR2 isoform of the ryanodine receptor. Cheng et al2 clearly favored the hypothesis that Ca2+ sparks arose from the opening of a single RyR, which would certainly be an "elementary event," because it would arise from one molecule. Of course, the possibility that Ca2+ sparks arose from a small number of RyR "acting in concert" could not be excluded by their data. The distinction between these possibilities is extremely important, however, for our understanding of the mechanism of SR Ca2+ release during E-C coupling. If, in fact, a Ca2+ spark arises from just one RyR, then we are left with the very puzzling question of why the others in the group are not activated by the Ca2+ released from one. Similarly, if they "act in concert," then the very interesting question of cooperativity among a large group of macromolecules arises. Much of the work appearing to establish Ca2+ sparks as elementary events of E-C coupling relied on accurately counting the numbers of Ca2+ sparks in confocal line-scan images. Sparks were typically identified subjectively, or on the basis of some arbitrary criterion, such as minimum spatial half-width or an amplitude threshold. This enabled counting Ca2+ sparks, and when such criteria were used, it appeared that spontaneous and evoked Ca2+ sparks were identical. Furthermore, the mean amplitude of (counted) evoked Ca2+ sparks was independent of voltage,3 a finding confirmed again recently.21 However, confocal line-scan images invariably show small changes in fluorescence that are difficult to categorize. Are these Ca2+ sparks occurring off the laser scan line, or are they different types of events of SR Ca2+ release? The possible existence of events of SR Ca2+ release different from Ca2+ sparks or yet smaller than Ca2+ sparks throws into question the notion of Ca2+ sparks as truly "elementary" events of E-C coupling. Furthermore, it was recognized early on that the limitations of confocal imaging will make it difficult to distinguish out-of-focus Ca2+ sparks from possible small Ca2+ sparks.30 31 At present, the question of the number of RyR and their gating pattern underlying cardiac Ca2+ sparks remains unresolved.32 Nevertheless, the theory of Ca2+ spark amplitude distributions is now better understood, both in cardiac muscle33 and in skeletal muscle.34 In addition, "automatic Ca2+ spark detection" programs29 33 can be used to eliminate bias of the observer. The best available data from analysis of Ca2+ spark amplitude distributions suggest that they represent a distribution of "source strengths."33 Here, "source strength" refers to the combination of RyR open time and current amplitude. At present, however, it cannot be distinguished reliably whether or not such Ca2+ spark amplitude distributions are fit better by a gaussian distribution or an exponential distribution of "source strengths."

The first substantive indication that cardiac Ca2+ sparks may not arise from single RyR came when multiple sites of origin were resolved in ventricular cells35 and in atrial cells.36 In ventricular cells, transverse scanning revealed multiple sites of origin, perhaps corresponding to separate clusters of RyR.

Ca2+ sparks with multiple sites of origin are distinct from the postulated Ca2+ quarks, which may represent release from single RyR. When SR Ca2+ release was evoked by photolysis of caged Ca2+ in the whole cell, Ca2+ sparks were not observed, leading to the suggestion that release occurred as unresolvable events.37 The existence of Ca2+ quarks was postulated, units of SR release smaller than Ca2+ sparks. This release gave rise to spatially uniform changes in Ca2+, a puzzling observation because of the lack of any known uniformly distributed SR Ca2+ release channels. When Ca2+ was released in a small volume by two-photon photolysis,38 small events of SR Ca2+ release were observed directly, for the first time. These were abolished by SR depletion (and therefore not due directly to photolytically released Ca2+) and were smaller in amplitude than typical Ca2+ sparks.

The original computations of the flux of Ca2+ underlying Ca2+ sparks was consistent with the idea that a Ca2+ spark could arise from a single RyR, if it was assumed that the flux through a single RyR was {approx}4 pA. However, the most recent data from lipid bilayer experiments under quasiphysiological conditions39 suggest that the unitary Ca2+ current should be <0.6 pA. This implies that multiple RyR are involved in the generation of a Ca2+ spark. Although comparisons between cardiac Ca2+ sparks and frog skeletal muscle Ca2+ sparks may not be valid, a detailed model of E-C coupling in this tissue suggests that Ca2+ sparks arise from multiple RyR.40 Recently, "coupled" gating of isolated RyR has been demonstrated,41 and the potential of "coordinated" gating of cardiac RyR to explain cardiac E-C coupling has been noted.42

Termination of the Ca2+ spark and/or refractoriness in spark generation is expected to be extremely important in E-C coupling. A mechanism must exist by which RyR are inactivated and not available to release Ca2+ again, in order for a Ca2+ transient to be produced. This mechanism appears not to be either SR depletion or "stochastic inactivation."43 44 Ca2+ release appears to be terminated by an "active extinguishing mechanism" such as Ca2+-dependent inactivation or adaptation. The possible roles in terminating release of the accessory proteins, sorcin and FKBP12, have been discussed recently.45


*    Other Putative Sources of Ca2+ to Trigger SR Ca2+ Release
up arrowTop
up arrowIntroduction
up arrow"Local Control" Theory of...
up arrowVisualization of Local SR...
*Other Putative Sources of...
down arrowPutative Protein Kinase A...
down arrowSummary
down arrowReferences
 
Although there is a consensus that the L-type Ca2+ current is the major trigger for SR Ca2+ release, other triggers have been suggested. In guinea pig ventricular myocytes, T-type Ca2+ current can trigger SR Ca2+ release, although much less efficiently than L-type.46 The ability of the Na+/Ca2+ exchanger to operate in the "reverse" mode and cause SR Ca2+ release has been reported in a number of mammalian ventricular cell types, most recently, in the study of Litwin et al.47 The location of the Na+/Ca2+ exchanger in the membranes of cardiac cells remains controversial,48 with some studies interpreted to show that exchanger molecules are located preferentially in t-tubules, whereas other studies are interpreted to show a more uniform distribution of exchanger molecules. Under experimental conditions during which L-type Ca2+ channels were open but not conducting, Ca2+ entry via "reverse" mode of the Na+/Ca2+ exchanger did not induce Ca2+ sparks but rather caused a slow uniform increase in [Ca2+]i throughout the cell.3 The activity of local Na+/Ca2+ exchange could set a local [Ca2+]i that would shift the sensitivity of the RyR to Ca2+ entering via L-type Ca2+ channels.47

Recently, a new and functionally distinct Na+ current component (ICa(TTX)) has been identified in rat ventricular cells.49 This new component displays different kinetics, different voltage ranges for both activation and inactivation, and different permeability properties from the classical cardiac Na+ channel. Specifically, ICa(TTX) activates over a more negative voltage range than classical cardiac Na+ channels and is highly permeable to Ca2+. Under nonphysiological experimental conditions (ie, Na+-free external and internal solutions), Ca2+ permeation of ICa(TTX) is capable of triggering SR Ca2+ release.50 These ICa(TTX)-evoked Ca2+ transients are delayed markedly in onset and have slower upstrokes compared with Ca2+ transients elicited by L-type Ca2+ currents of similar current density. It is not yet known whether ICa(TTX) channels are permeable to Ca2+ in the presence of physiological concentrations of Na+. To the extent that ICa(TTX) is relevant to E-C coupling, it will probably have a modulatory role rather than provide a major component of the Ca2+ trigger for SR Ca2+ release and the "gain" of cardiac E-C coupling.

A tetrodotoxin (TTX)-blockable Ca2+ current has been reported51 in rat ventricular myocytes after several pharmacological treatments (cAMP, isoproterenol [ISO], or the cardiotonic steroids, ouabain and digoxin), and this current appears capable of triggering Ca2+ sparks. This TTX-blockable Ca2+ current was attributed to a Ca2+ permeability induced in classical cardiac Na+ channels that are normally impermeable to Ca2+. Treated Na+ channels were then said to be "promiscuous." Although intriguing, these results are as yet unconfirmed, and two separate lines of experimental evidence challenge the conclusion of cAMP-induced Ca2+ permeability of classical cardiac Na+ channels. (1) In voltage-clamped rat ventricular cells, Balke et al52 and Goldman et al53 have shown that ISO substantially increases the TTX-blockable Ca2+ current. Importantly, all of this induced current flows through ICa(TTX) channels and not through classical Na+ channels, because the ISO-mediated increase in ICa(TTX) was not accompanied by a reduction in INa as would be required. Therefore, these experiments are not consistent with a change in selectivity of classical Na+ channels induced by conditions that promote channel phosphorylation. These experiments are in agreement with findings in guinea pig,54 rabbit,55 and canine ventricular myocytes,56 as well as in rat cardiac Na+ (SkM2) channels expressed heterologously in frog oocytes.57 (2) In Chinese hamster ovary cells overexpressing {alpha} subunits of the cardiac Na+ channels both with and without ß1 subunits, Nuss and Marbán58 59 have shown that the well-described ISO-mediated increase in INa was completely occluded with removal of external Na+ in the continued presence of external Ca2+. In cells expressing both {alpha} and ß1 subunits in Na+- and Ca2+-containing external solutions, Na+ conductance increased with ISO but without any changes in reversal potential. In these experiments, neither ß1 coexpression or the presence of external Na+ conferred Ca2+ permeability on classical cardiac Na+ channels. However, Cruz et al60 demonstrated a significant shift in reversal potential with dbcAMP in HEK293 cells expressing either the {alpha} and ß1 subunit or the {alpha}, ß1, and ß2 subunits of the Na+ channel.


*    Putative Protein Kinase A–Dependent Voltage-Sensitive Ca2+ Release Mechanism (VSRM)
up arrowTop
up arrowIntroduction
up arrow"Local Control" Theory of...
up arrowVisualization of Local SR...
up arrowOther Putative Sources of...
*Putative Protein Kinase A...
down arrowSummary
down arrowReferences
 
Recently, it has been postulated that a component of SR Ca2+ release in mammalian cardiac muscle is activated by changes in membrane voltage or to be "sensitive" to membrane voltage.6 61 62 These experiments have been performed under different conditions than used earlier, in which the detailed relationship between ICa and SR Ca2+ release was studied through the use of holding potentials that inactivated INa and permitted good control of membrane voltage during voltage-clamp pulses. Although temperature and internal monovalent cations (K+ versus Cs+) were once thought to be important in observing VSRM, it now appears that the most important conditions for observing VSRM (in dialyzed cells) are the inclusion of cAMP and the use of relatively negative prepulse potentials.63 In these experiments, whole-cell L-type Ca2+ currents and Ca2+ transients (or contraction) are measured at 37°C in single adult rat, rabbit, or guinea pig ventricular cells. Typically Na+ channels are inhibited with lidocaine (300 µm), and Ca2+ entry via Na+/Ca2+ exchange is prevented with Na+-free pipette solutions. In the presence of 8-Bromo-cAMP, a two-step protocol (from -65 to -40 to 0 mV) elicits two contractions, of approximately equal magnitude.63 In this "two-step" protocol, the first contraction (elicited by depolarization to -40 mV) is absent if cAMP is absent but persists in the presence of Ca2+ channel blockers (Cd2+). The second is absent if Ca2+ channels are blocked but persists in the absence of cAMP and the use of relatively positive holding potentials (-40 mV). Because the putative VSRM was shown to be completely inactivated at -40 mV,63 the two-step protocol is thought to produce an initial contraction (at -40 mV) that is dependent solely on the VSRM and does not require Ca2+ entry via Ca2+ channels, whereas the second (to 0 mV) is thought to produce a contraction that is dependent solely on Ca2+ entry. In earlier work, it was shown that ryanodine (30 nmol/L) abolished the VSRM contraction but not those triggered by ICa, and that the VSRM contractions were abolished in the total absence of external Ca2+ but persisted in the presence of external [Ca2+] of 50 µmol/L. It is not known yet whether such release might occur via Ca2+ sparks.

The experiments described above are intriguing, but we have several reservations about them. (1) Voltage-activated Ca2+ release should occur in the absence of external Ca2+. This has not been demonstrated adequately in any of the experiments cited above. On the contrary, Nabauer et al64 have already shown (rather convincingly) that contractions elicited by clamp pulses from -60 mV (and more negative) to 0 mV fail completely after switching rapidly to Ca2+ free solutions. Most importantly, neither Na+ nor Ba2+, which do flow through L-type Ca2+ channels and which do support voltage-activated Ca2+ release in skeletal muscle, was capable of eliciting contraction. These elegant and conclusive experiments64 should be repeated in the presence of high concentrations of intracellular cAMP. (2) Ca2+ channels are not totally unavailable at -40 mV and therefore, steps to -40 mV will activate L-type Ca2+ channels, particularly in the highly potentiated state produced by high concentrations of cAMP. The small currents flowing at -40 mV should be identified unequivocally. (3) The VSRM should be studied mainly at positive potentials, where it is well established that Ca2+ entry is not sufficient to trigger contraction, but a VSRM should be fully activated. In fact, recent work65 using similar conditions to those used by Ferrier et al6 failed to show Ca2+ release at very positive membrane potentials. (4) The amount of contraction in the experiments cited above is relatively small. For example, contractions were only about 3 µm at 0 mV from -65 mV with 50 µmol/L cAMP (Figure 10 of Reference 6363 ). Such small contractions, under such highly potentiated conditions, are puzzling. (5) The L-type Ca2+ currents in the presence of 50 µmol/L cAMP are extremely large (eg, 7 nA, Figure 1 of Reference 6363 ). Under these conditions, the SR must be highly loaded, particularly because the SERCA will be highly stimulated. Under these conditions, it may be "trigger happy." Regenerative releases could be stimulated by the opening of just a few Ca2+ channels. (6) It will be difficult to study the putative VSRM selectively, because any release activated by voltage may inevitably be amplified by CICR. In frog skeletal muscle, the voltage-activated release is thought to provide the initial change in Ca2+ that activates the RyR, via CICR, that are not facing voltage sensors.40 It is not possible to separate totally one type of release from the other. (7) Ca2+ transients should be measured, and the rate of SR Ca2+ release flux should be calculated.10 29 Maximum shortening is not a reliable indicator of the peak rate of SR Ca2+ release in mechanically unloaded myocytes. (8) Organic L-type Ca2+ channel blockers should be compared with the inorganic blockers (Cd2+, Ni2+, and Co2+), because the mode of block of these substances is quite different. (9) The experiments demonstrating VSRM in dialyzed cells use cAMP in the intracellular perfusion solution, and L-type Ca2+ currents are very large. We wonder, therefore, whether cells in such a condition are capable of responding further to ß1-agonist stimulation. Within the living organism, the heart is capable of increasing output substantially over basal levels as a result of ß1-agonist stimulation. If cells demonstrating VSRM are not responsive to ß1-agonist stimulation, the implication is that the VSRM is not important in normal E-C coupling in the basal state.

From the above, we conclude that, if VSRM exists in cardiac muscle, it must differ substantially from voltage-activated release in skeletal muscle. Finally, the difficulty of controlling or regulating such a putative mechanism has been pointed out recently.66


*    Summary
up arrowTop
up arrowIntroduction
up arrow"Local Control" Theory of...
up arrowVisualization of Local SR...
up arrowOther Putative Sources of...
up arrowPutative Protein Kinase A...
*Summary
down arrowReferences
 
The body of experimental work on E-C coupling in normal cardiac muscle supports a number of conclusions. (1) Ca2+ entry via L-type Ca2+ channels is the predominant source of the Ca2+ that triggers SR Ca2+ release under conditions that support normal E-C coupling. (2) Whole-cell L-type Ca2+ currents and whole-cell Ca2+ transients can be understood in terms of the recruitment and summation of their respective independent local events (namely, single L-type Ca2+ currents and Ca2+ sparks). (3) Ca2+ sparks almost certainly arise from Ca2+ released from a cluster of RyR. (4) The local [Ca2+] in the region of the RyR is undoubtedly determined by several molecular species, including the L-type Ca2+ channels, the RyR themselves, the Na/Ca exchanger, Na+ channels, Ca2+ pumps, and others. It is important to note that spontaneous Ca2+ sparks do occur in mammalian cardiac muscle under physiological conditions.67 Thus, the concepts derived from single-cell studies appear to be relevant to the intact tissue.


*    Footnotes
 
1 This MiniReview is part of a thematic series on Calcium Cycling in Cardiovascular Cells, which includes the following articles:

Ca2+ Release Mechanisms, Ca2+ Sparks, and Local Control of Excitation-Contraction Coupling in Normal Heart Muscle

Interactions Between Ca2+ and H+ and Functional Consequences in Vascular Smooth Muscle Cells

Intracellular Calcium Release Channels Calcium Fluxes Involved in Control of Cardiac Myocyte Contraction

C. William Balke, Guest Editor Back

Received July 2, 1999; accepted August 25, 1999.


*    References
up arrowTop
up arrowIntroduction
up arrow"Local Control" Theory of...
up arrowVisualization of Local SR...
up arrowOther Putative Sources of...
up arrowPutative Protein Kinase A...
up arrowSummary
*References
 
1. Fabiato A. Calcium-induced release of calcium from the sarcoplasmic reticulum. J Gen Physiol. 1985;85:189–320.[Abstract/Free Full Text]

2. Cheng H, Lederer WJ, Cannell MB. Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle. Science. 1993;262:740–744.[Abstract/Free Full Text]

3. Lopez-Lopez JR, Shacklock PS, Balke CW, Wier WG. Local calcium transients triggered by single L-type calcium channel currents in cardiac cells. Science. 1995;268:1042–1045.[Abstract/Free Full Text]

4. Cannell MB, Cheng H, Lederer WJ. The control of calcium release in heart muscle. Science. 1995;268:1045–1049.[Abstract/Free Full Text]

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D. A. Eisner and A. W. Trafford
No Role for the Ryanodine Receptor in Regulating Cardiac Contraction?
Physiology, October 1, 2000; 15(5): 275 - 279.
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Circ. Res.Home page
D. M. Bers
Calcium Fluxes Involved in Control of Cardiac Myocyte Contraction
Circ. Res., August 18, 2000; 87(4): 275 - 281.
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Circ. Res.Home page
T. Kaneko, H. Tanaka, M. Oyamada, S. Kawata, and T. Takamatsu
Three Distinct Types of Ca2+ Waves in Langendorff-Perfused Rat Heart Revealed by Real-Time Confocal Microscopy
Circ. Res., May 26, 2000; 86(10): 1093 - 1099.
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J. Biol. Chem.Home page
P. R. Territo, S. A. French, M. C. Dunleavy, F. J. Evans, and R. S. Balaban
Calcium Activation of Heart Mitochondrial Oxidative Phosphorylation. RAPID KINETICS OF mVO2, NADH, AND LIGHT SCATTERING
J. Biol. Chem., January 19, 2001; 276(4): 2586 - 2599.
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V. Piacentino III, J. P. Gaughan, and S. R. Houser
L-Type Ca2+ Currents Overlapping Threshold Na+ Currents: Could They Be Responsible for the "Slip-Mode" Phenomenon in Cardiac Myocytes?
Circ. Res., March 8, 2002; 90(4): 435 - 442.
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Circ. Res.Home page
M. Jane Lalli, J. Yong, V. Prasad, K. Hashimoto, D. Plank, G. J. Babu, D. Kirkpatrick, R. A. Walsh, M. Sussman, A. Yatani, et al.
Sarcoplasmic Reticulum Ca2+ ATPase (SERCA) 1a Structurally Substitutes for SERCA2a in the Cardiac Sarcoplasmic Reticulum and Increases Cardiac Ca2+ Handling Capacity
Circ. Res., July 20, 2001; 89(2): 160 - 167.
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Circ. Res.Home page
V. Lukyanenko, I. Gyorke, T. F. Wiesner, and S. Gyorke
Potentiation of Ca2+ Release by cADP-Ribose in the Heart Is Mediated by Enhanced SR Ca2+ Uptake Into the Sarcoplasmic Reticulum
Circ. Res., September 28, 2001; 89(7): 614 - 622.
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Circ. Res.Home page
M. Lohn, W. Jessner, M. Furstenau, M. Wellner, V. Sorrentino, H. Haller, F. C. Luft, and M. Gollasch
Regulation of Calcium Sparks and Spontaneous Transient Outward Currents by RyR3 in Arterial Vascular Smooth Muscle Cells
Circ. Res., November 23, 2001; 89(11): 1051 - 1057.
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