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(Circulation Research. 2003;92:e45.)
© 2003 American Heart Association, Inc.

Response to Research Commentary

Cyclic Variation of Intracellular Calcium

A Critical Factor for Cardiac Pacemaker Cell Dominance

Edward G. Lakatta, Victor A. Maltsev, Konstantin Y. Bogdanov, Michael D. Stern, Tatiana M. Vinogradova

From the Gerontology Research Center, Baltimore, Md.

Correspondence to Edward G. Lakatta, MD, Gerontology Research Center, 5600 Nathan Shock Dr, Box 13, Baltimore, MD 21224. E-mail LakattaE{at}grc.nia.nih.gov

Abstract

While a diversity of cell types and distribution within the sinoatrial node and cell-cell interactions add complexity to a complete elucidation of the heart’s pacemaker function, it has become clear that cyclic variation of submembrane [Ca²⁺] and activation of the Na⁺-Ca²⁺ exchanger during diastolic depolarization (DD) act in concert with ion channels to confer on sinoatrial node cells (SANCs) their status of dominance with respect to pacemaker function. Studies using confocal microscopy indicate that subsarcolemmal Ca²⁺ release via ryanodine receptors occurs not only in response to the action potential (AP) upstroke, but also during the DD, and this is augmented by ß-adrenergic receptor (ß-AR) stimulation. Spontaneous APs simulated by mathematical SANC models beat at a faster rate when this subsarcolemmal Ca²⁺ waveform measured under ß-AR stimulation is introduced into the modeling scheme. Thus, in future investigation of pacemaker functioning in health, disease, and disease therapies the "bar ought to be raised" to embrace the impact of cyclic variation in submembrane [Ca²⁺] on pacemaker function. The full text of this article is available at http://www.circresaha.org.

Key Words: sinoatrial node • ß-adrenergic stimulation • ryanodine receptor • submembrane Ca²⁺ release

In pacemaker parlance, "dominance" refers to those excitable cells with "clocks" having the briefest periods, thereby allowing these cells to "capture" or drive other excitable cells, leading to a heart beat. Sinoatrial node cells (SANCs) achieve a dominant status because they exhibit shorter intervals between spontaneous action potentials (APs) than do atrial, atrioventricular nodal, or His-Purkinje cells. In SANCs,¹ as in most excitable cells, voltage- and time-dependent transmembrane ion fluxes are also regulated by ion channels and carriers and their modulation by intracellular Ca²⁺ and phosphorylation. Studies using intracellular Ca²⁺-sensitive indicators, coupled to confocal imaging and simultaneous measurement of membrane potential or current, have been interpreted to indicate that cyclic variation in submembrane Ca²⁺ coupled to Na⁺-Ca²⁺ exchanger (NCX) activation modulates this SANC beating rate and is a factor in establishing SANC dominance in pacemaker function.

Like other excitable cells, SANCs cycle Ca²⁺ into and out of their sarcoplasmic reticulum (SR). Activation of ryanodine receptors (RyRs), the SR Ca²⁺ release channel, like that of many other classically described sarcolemmal ion channels, is cyclically regulated by time- and Ca²⁺-dependent gating mechanisms.^2,3 Upon activation, RyRs release Ca²⁺ into a narrow cleft beneath the SANC sarcolemma at two distinct times during each spontaneous SANC duty cycle (Figure 1): in response to the AP rapid upstroke, as in ventricular myocytes, and during the later part of spontaneous diastolic depolarization (DD) before the next AP upstroke. Several time- and voltage-dependent ion currents that become activated during the DD, ie, T-type and L-type Ca²⁺ currents (I_Ca,T, I_Ca,L), hyperpolarization-activated inward current (I_f), chloride current, the rapid component of delayed rectifier K⁺ current (I_Kr), a time-independent background current carried by Na⁺, and NCX are Ca²⁺-dependent and therefore may link RyR Ca²⁺ release from the SR to DD modulation. In their Research Commentary "Sarcoplasmic Reticulum Ca²⁺ Release Is Not a Dominating Factor in Sinoatrial Node Pacemaker Activity," Honjo et al⁴ question the relevance of RyR Ca²⁺ release to cardiac chronotropy and its modulation by ß-adrenergic receptor (ß-AR) stimulation.

View larger version (20K): [in this window] [in a new window]   Figure 1. Variation of subsarcolemmal [Ca2+] defined by confocal line-scan (inset) images of SANCs (inset) in the presence or absence of 3 µmol/L Ry (top) or 0.1 µmol/L ISO (bottom) tracings and simultaneous membrane potential is depicted. F/F0 is the instantaneous fluorescence of the Ca2+ indicator, fluo-3, relative to its minimal fluorescence (F0) and other experimental conditions are as previously published.9,19 Note that in the predrug control state, the Ca2+ waveform exhibits an increase, during the later part of the spontaneous DD (bracketed by arrows and shown at greater resolution in rightmost panels). This DD component of the Ca2+ waveform is abolished by Ry and augmented by ISO, concurrent with a slowing or acceleration of the beating rate, respectively, by the former and latter drug.

What Role Does RyR Ca²⁺ Release-NCX Activation Have in Pacemaker-Cell Dominance?

A critical dependence of cardiac pacemaker regulation on RyR Ca²⁺ release-NCX activation becomes manifest early during development. The normal increase in heart rate with differentiation is markedly depressed in cardiac myocytes differentiated in vitro from embryonic stem (ES) cells with a functional knockout (KO) of the RyR₂ that exhibit markedly depressed DD slope.⁵ Exposure of wild-type ES cells to ryanodine (Ry), which at low concentration locks RyRs in a subconductance state, confers on these cells the properties of RyR KO cells. NCX KO mice die in embryo without evidence of the heart ever beating.⁶

A dependence of spontaneous beating rate on intracellular Ca²⁺ and RyR function and NCX activation has been demonstrated to occur in adult pacemaker cells and tissue.^7–15 In the adult heart, nodal and conduction tissues abundantly express the NCX.¹⁶ A relatively large inward current, second only to I_Ca,L in maximum amplitude, produced by NCX operating in the "forward" mode (extruding Ca²⁺ for 3 Na⁺) during the DD of pacemaker cells is now recognized as a key factor in pacemaker function,^7–9 and rhythmic activity of pacemaker model simulation¹⁷ ceases when NCX current is removed. Studies using confocal imaging in rabbit SANCs have shown that distorting or preventing the subsarcolemmal Ca²⁺ waveform in rabbit SANCs by chelation of intracellular Ca²⁺ in adult SANCs with BAPTA¹⁸ or interfering with RyR Ca²⁺ release with Ry reduces the spontaneous beating rate.⁹ Disabling the NCX experimentally prevents spontaneous SANC firing.⁹

The effect of Ry to concurrently abolish the component of subsarcolemmal Ca²⁺ release during the DD and reduce the spontaneous beating rate in a representative rabbit SANC is shown in Figure 1. All studies that have used Ry in cardiac pacemaker cells or tissue, have, in fact, observed a reduction of the spontaneous beating rate of pacemaker cells or tissue (Table 1). In our opinion, the most important finding of Honjo et al⁴ is that Ry, indeed, reduced the spontaneous firing rate in isolated intact sinoatrial node (SAN) and single SANC, by 19% and 22%, respectively (Table 1), indicating that RyR Ca²⁺ release is indeed a critical determinant of the maximum beating rate and therefore, of their dominant pacemaker status.

View this table: [in this window] [in a new window]   Table 1. Effect of Ry on the Spontaneous Beating Rate of Isolated SAN Tissue or Single SANC

ß-AR Stimulation Chronotropy in Pacemaker Cells
ß-AR stimulation, a potent physiological mechanism to accelerate the beating rate of pacemaker cells, recruits additional RyRs to release Ca²⁺ during the DD,¹⁹ activating NCX current to a greater extent, and thus increasing the DD amplitude (Figure 1, bottom traces). Several recent studies^15,20–22 indicate that the full effect of ß-AR stimulation to enhance the rate of pacemaker depolarization and to increase the beating rate, does, in fact, require intact RyR function (Table 2). Specifically, partial inhibition of normal RyR function by low concentrations of Ry, which results in SR Ca²⁺ depletion, blunts the effect of isoproterenol (ISO) to increase the beating rate, but does not always abolish the ISO chronotropic effect.^15,19–22 The link between the ß-AR chronotropic effect and cyclic variation in cell Ca²⁺ is attributable, in part, to a ß-AR stimulation–induced increase in protein kinase A–dependent phosphorylation of L-type Ca²⁺ channels, phospholamban, and RyRs. An increase in Ca²⁺ flux of L-type Ca²⁺ channels during ß-AR stimulation also accelerates removal of L-type Ca²⁺ channel inactivation by Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) and enables these channels to be more responsive to a given DD.¹⁸ Thus, at least two Ca²⁺-dependent mechanisms, removal of L-type channel inactivation via CaMKII and RyR Ca²⁺ release to augment an inward current via NCX activation to augment depolarization, complement each other with respect to modulation of the DD and the beating rate of SANCs in response to ß-AR stimulation. Ca²⁺-dependent modulation of other SANC ion channels likely occurs during ß-AR stimulation, but the relevance of this with respect to the ß-AR stimulation–induced increase in spontaneous beating rate requires further study.²³

View this table: [in this window] [in a new window]   Table 2. Effect of Ry on the Increase in Pacemaker Beating Rate After ß-AR Stimulation

Honjo et al,⁴ in contrast to the results of multiple studies (Table 2), maintain that the effect of ß-AR stimulation to increase the pacemaker firing rate does not require intact RyR function. They report that ISO could still augment the spontaneous beating rate in the presence of Ry. Generally, this is not inconsistent with the studies in Table 2, but because Honjo et al studied only a single ISO dose after exposure to Ry, and because no data are provided on the effect of ISO before Ry, their results cannot be directly compared with these other studies. It is noteworthy that the very high concentration of Ry (30 µmol/L) used by Honjo et al is higher than that in most previous studies (Table 2). Interestingly, one previous study found that ISO could overcome the effects of high (but not low) concentrations of Ry.²¹

Can a Single Factor Within Pacemaker Cells Confer Dominance?
A reductionist approach attempts to dissect the interactions that occur among a multitude of factors involved in pacemaking to determine which factor that influences membrane potential is the most important with respect to pacemaker function. In this context, Honjo et al⁴ declare that SR Ca²⁺ release is not a dominating factor in SAN pacemaker activity because RyRs reduce the beating rate of isolated SA nodal tissue or cells they have isolated from the SA node by 20%. It is clear from the results of studies in Tables 1 and 2 that although classically studied ion currents are required to ensure spontaneous firing of SANCs, and critically contribute to the dominance of their pacemaking activity, none of these channels, per se, is sufficient to ensure a maximal firing rate (dominance) under a given ambient condition. Cyclic Ca²⁺ release via RyRs, however, is required to achieve the most rapid beating rate that can occur. Whether interference with RyR Ca²⁺ release reduces beating rate of the SA node by 20% or 100% (Table 1) is irrelevant. Thus, in contrast to Honjo et al,⁴ we interpret their data and that prevalent in the literature (Tables 1 and 2) to conclude that the RyR Ca²⁺ release-NCX activation is necessary, but not sufficient, for pacemaker cells to achieve dominance.

Diversity of Ca²⁺ Dependence of Cell Types Within the SAN
There is some evidence to indicate that cells within the SAN are not unique in nature or distribution^24,25 and that the dominance of a given cell type within the SAN may shift to other cell types in response to various stimuli, eg, ß-AR stimulation. Honjo et al⁴ suggest that SANC type diversity may provide a plausible explanation for the differences observed among studies in Table 1 with respect to the effectiveness of Ry to influence the spontaneous beating rate and its response to ß-AR stimulation. Specifically, they suggest that cells in the central area of the SAN, ie, sometimes referred to as "primary pacemaker cells," have fewer RyRs than do other cells within the SAN and are therefore less Ca²⁺-dependent than other SANC types. That Ry induced only a 20% decrease in the beating rate of the cells on which they report² has been interpreted to indicate that these cells likely represent central or primary pacemaker cells and exhibit little Ca²⁺ dependence of their beating rate. Although this hypothesis is plausible, it would have been instructive if Honjo et al were also to have examined whether chelation of intracellular Ca²⁺, eg, with intracellular BAPTA,¹⁸ or whether abrogating the effectiveness of the "partner" of the RyR, ie, the NCX, reduced the beating rate of cells they had studied. In short, it is our opinion that additional studies are required to precisely delineate the primary pacemaker site within the SAN in the study of Honjo et al⁴ and to define the extent to which Ca²⁺-dependent mechanisms affect the beating rate of different cell types comprising the SAN.

Are Contemporary Pacemaker Models Lacking a Subsarcolemmal Ca²⁺ Waveform Sufficiently Robust to Define Pacemaker Cell Dominance?
Another basis for the position of Honjo et al⁴ that SR Ca²⁺ release is unimportant in primary pacemaker cells arises from observations that mathematical model simulations of these cells exhibit spontaneous beating in the absence of consideration of a cyclicly varying subsarcolemmal Ca²⁺ waveform. Their numerical pacemaker model²⁶ and most other models do not embrace the well-known concept of Ca²⁺-dependent modulation of ion channels and in extreme cases do not consider cyclic changes in intracellular [Ca²⁺] (or other ion concentrations), assuming the intracellular [Ca²⁺] to be constant.²⁶ To test whether a submembrane Ca²⁺ waveform is a crucial determinant of the dominant pacemaker status of central SANCs studied by Honjo et al,⁴ we have integrated a Ca²⁺ waveform measured in our experiments by confocal microscopy in an ISO-stimulated SANC, ie, similar to that in Figure 1 to their own numerical model for primary pacemaker cells.²⁶ We observed that the spontaneous APs generated by the model were quickly entrained and driven to beat at a 17% higher rate, ie, at the rate of oscillatory Ca²⁺ waveform that we integrated into their model (Figure 2). This result indicates that coupling of the RyR-generated Ca²⁺ waveform (Figure 2B, right) to the NCX current (Figure 2C), the only Ca²⁺-dependent component included in the model,²⁶ is sufficient to increase the beating rate via acceleration of DD (Figure 2D). This result directly refutes the conclusion of Honjo et al⁴ that intact RyR function is not required in central SANCs for a fuel response to ß-AR stimulation. We also found similar accelerating effects of an oscillating Ca²⁺ waveform on AP firing rate in a numerical SANC model by Demir et al.²⁷

View larger version (67K): [in this window] [in a new window]   Figure 2. Experimentally measured subcellular Ca2+ waveform accelerates the beating rate of spontaneous APs simulated by a numerical model for primary pacemaker cells.26 A through C, left panels, Original model parameters with [Ca2+] held constant drives the first 7 seconds of spontaneous APs and NCX current. When 4 cycles of a subsarcolemmal Ca2+ waveform, measured experimentally in the presence of ISO, are integrated into the model and iterated continuously, the NCX current increases by 2-fold and the rate of spontaneous APs increases by 17% (right panels of A through C). Panel D illustrates on the slower time base the effect of the Ca2+ waveform on AP period (left and middle) as well as its effect to accelerate DD (right panel).

Moreover, we observed that the numerical model for primary pacemaker cells presented by Zhang et al,²⁶ which does not embrace an oscillatory Ca²⁺ waveform, lacks physiological robustness, because it fails to generate rhythmic APs when the initial membrane voltage is set within a physiologically relevant range, ie, close to 50 mV, with background [Ca²⁺] held constant at different levels (Figure 3). However, when an experimentally measured Ca²⁺ waveform similar to the control SANC Ca²⁺ waveform in Figure 1 is integrated into the model, robust beating is restored in the context of the very same initial conditions. Figure 3 also illustrates the fact that Ca²⁺ oscillations, per se, and not a steady [Ca²⁺], are important for the Ca²⁺-dependent effect to permit the generation of repetitive APs under these initial conditions, because the study in the aborted beating in Figure 3A was set at the same level (265 nmol/L) as the average [Ca²⁺] in Figure 3B. This suggests to us that a cyclic variation in Ca²⁺ is required for robust maintenance of spontaneous beating, under some conditions, at least.

View larger version (33K): [in this window] [in a new window]   Figure 3. Generation of an intracellular Ca2+ waveform ensures stable AP firing in the numerical pacemaker model,26 which fails to generate rhythmic APs at an initial membrane potential of -49 mV with [Ca2+] held constant (A). Augmented NCX current and rhythmic APs are generated by the same model (B) when it is supported by an experimentally measured subsarcolemmal Ca2+ waveform.

The marked effects of introduction of the Ca²⁺ waveform into the model simulations in Figures 2 and 3 could be explained by a low density of many aforementioned sarcolemmal ion channels in central SANCs, which have a very small 20-pF electrical capacitance.²⁶ In such cells, even a relatively small change in ion current balance, eg, due to an increased Ca²⁺-dependent current via NCX activation (Figure 2C) can notably change the total membrane electrical charge, resulting in a significant change of membrane potential. Thus, the ion current balance in these cells may be such that even fewer RyR or NCX molecules are required in central versus peripheral SANCs with respect to Ca²⁺ modulation of their firing rate. Although the results of Figures 2 and 3 show that an intracellular Ca²⁺ waveform is a critical factor in determining modeled pacemaker dominance, the contrary (that beating rate and dominance are adequately explained without considering changes in intracellular Ca²⁺) cannot be argued because of the relatively primitive state of pacemaker modeling. Existing models are based on phenomenological (rather than microscopically validated) representations of individual currents, neglecting important phenomena such as ion-dependent inactivation and mode shifts of Ca²⁺ channels. Because spontaneous APs are the result of a delicate balance of currents, large changes in the beating rate (or cessation of beating altogether) can be produced by modest changes in model parameters. Modelers have often felt free to adjust parameters to achieve the desired rates. Presently, there are no SANC models that incorporate a modern understanding of the mechanisms of intracellular Ca²⁺ via RyRs or the role of local intracellular Ca²⁺ gradients. It is our opinion that much work remains to be done to bring state-of-the-art pacemaker models to the stage where they can be used to test physiological questions.

Overdriving the Cyclic Ca²⁺ Waveform of SANCs
From Figures 1, 2, and 3, any external depolarizing influence (eg, that emanating from an artificial pacemaker or that arising from tweaking of pacemaker model parameters) that occurs after a prior AP with a period shorter than that of the DD component of the Ca²⁺ waveform might be expected to override the effect of the subsarcolemmal Ca²⁺ increase during DD, "capture" the beating frequency, and thus become a critical factor with respect to pacemaker dominance. Figure 4 shows that the beating rate of a SANC can indeed be captured by an external pacemaker that "overdrives" Ca²⁺ releases during DD, changing the instantaneous relationship between the changes in subsarcolemmal [Ca²⁺] and membrane potential.

View larger version (30K): [in this window] [in a new window]   Figure 4. External pacemaker captures the beating rate of an isolated, spontaneously beating SANC. A, Line-scan image of fluo-3 fluorescence with superimposed APs of the first and last beats in a representative SANC. External electrical stimulation through a patch pipette was initiated at beat 3, at a rate just higher than the spontaneous beating rate (see black arrows). The two spontaneous beats before initiation of external stimulation reveal the occurrence of the subsarcolemmal Ca2+ increase during the DD (A), which drives the trajectory of membrane potential versus calcium concentration (F/F0) in a counterclockwise loop (B). Note that by beat 5, the pre-AP increase in Ca2+ is precluded by the early occurrence of the externally driven AP, shifting the trajectory of membrane potential versus Ca2+ to a clockwise loop, similar to that seen during the duty cycle of normal ventricular myocytes (C).

Summary

On the basis of the results of many recent studies^{8–15,19–23} in addition to our recent studies^9,19 featured in the Research Commentary of Honjo et al,⁴ we envision that the maximum spontaneous beating rate of pacemaker cells (dominance) is a result of cyclic variation of subsarcolemmal Ca²⁺ produced by the release of Ca²⁺ from the SR via RyRs acting in concert with the NCX and an ensemble of sarcolemmal ionic channels to regulate the SANC DD oscillations (Figure 5). The cyclic changes in Ca²⁺ during the DD impart physiological robustness (stability) to the oscillating sarcolemmal ion currents and strengthens responses to hormonal regulation. Because RyR Ca²⁺ release occurs simultaneously with spontaneous DD before the rapid upstroke of the subsequent AP in SANCs, it has been suggested that voltage-dependent Ca²⁺ currents in at least one pacemaker cell type act as a trigger for this Ca²⁺ release.⁸ Voltage-independent Ca²⁺ release via RyRs, however, has also been demonstrated to occur within other cardiac cell types (see review²⁸). In ventricular myocytes, for example, voltage-independent SR Ca²⁺ release can induce sarcolemmal DD mainly via Ca²⁺ modulation of NCX exchanger, resulting in "abnormal automaticity."²⁹ A similar voltage-independent mechanism of RyR Ca²⁺ release, therefore, may also exist within SANCs to modulate their "normal automaticity." Additional studies to probe this hypothesis are warranted.

View larger version (27K): [in this window] [in a new window]   Figure 5. Schematic to depict the late diastolic component of the subsarcolemmal Ca2+ and membrane potential of SANCs, before or after ß-AR stimulation by ISO, on the basis of previously published results,9,19 and the timing of activation of an ensemble of sarcolemmal ion channels (in the absence of ISO), as reported in the literature. The dashed line is an extension of the DD after the maximum diastolic potential. The deviation of the actual membrane potential from the dashed line occurs concomitantly with an increase in subsarcolemmal [Ca2+], due to RyR release (shaded areas). After ISO, this deviation exhibits a phase shift, ie, its initial trajectory occurs earlier than in control, due largely to enhanced Ca2+ activation of the NCX current, and drives the membrane potential to the threshold required for AP, firing at an earlier time. Critical influences of If and IKr mostly occur before the period of the shaded area; ICa,T is activated before and during the earlier part of the shaded area. ICa,L begins to activate during the later part of the shaded area and explosively activates during the rapid AP upstroke.

Received October 28, 2002; revision received December 10, 2002; accepted December 30, 2002.

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