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News Physiol Sci 16: 101-106, 2001;
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News in Physiological Sciences, Vol. 16, No. 3, 101-106, June 2001
© 2001 Int. Union Physiol. Sci./Am. Physiol. Soc.

Intracellular Ca2+ Release Sparks Atrial Pacemaker Activity

Stephen L. Lipsius, Jörg Hüser and Lothar A. Blatter

S. L. Lipsius and L. A. Blatter are in the Department of Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153. J. Hüser is at Bayer AG, 42096 Wuppertal, Germany.

   Abstract
 
Electrical excitation of the mammalian heart originates from specialized pacemaker cells in the right atrium. Pacemaker activity depends on multiple ion channels and transport mechanisms that reside primarily within the plasma membrane. However, recent evidence indicates that intracellular Ca2+ release from the sarcoplasmic reticulum also contributes importantly to atrial pacemaker function.


   Introduction
Top
 Introduction
Multiple mechanisms contribute...
 Ca2+ release from the...
 T-type Ca2+ current
 Na+/Ca2+ exchange current
 Low-voltage-activated diastolic...
 Structure-function relationship
 Conclusions
 References
 
The heartbeat is normally controlled by the primary pacemaker of the heart, i.e., the sinoatrial (SA) node. Classically, the SA node is viewed as a relatively well defined group of specialized cells located at the junction of the superior vena cava and the right atrial appendage. The exact site of dominant pacemaker activity can shift among cells within the SA node region in response to various external factors that normally affect heart rate, such as autonomic nerve stimulation. The heart also contains secondary or latent atrial pacemakers located outside of the SA node in well defined regions of the inferior right atrium at its junction with the inferior vena cava (9). These atrial pacemakers can assume control of the heartbeat in the event of SA node failure and may also compete with primary pacemaker activity, thereby contributing to abnormal atrial rhythms, i.e., atrial arrhythmias. Although the electrical activities of both SA node and latent atrial pacemaker cells depend primarily on ion channels and transporters that reside within the plasma membrane, recent work (6) indicates that local subsarcolemmal release of intracellular Ca2+, i.e., Ca2+ sparks (2), also contributes significantly to atrial pacemaker function. This intracellular Ca2+ release is triggered by voltage-dependent activation of T-type Ca2+ channels and is thought to stimulate inward Na+/Ca2+ exchange current (INa/Ca) to depolarize the membrane toward the action potential threshold. This review focuses primarily on the Ca2+-mediated mechanisms that participate in latent atrial pacemaker activity.


   Multiple mechanisms contribute to the pacemaker potential
Top
 Introduction
 Multiple mechanisms contribute...
Ca2+ release from the...
 T-type Ca2+ current
 Na+/Ca2+ exchange current
 Low-voltage-activated diastolic...
 Structure-function relationship
 Conclusions
 References
 
Cardiac pacemaker cells exhibit the property of automaticity as a result of a gradual depolarization of the membrane potential during electrical diastole, i.e., diastolic depolarization or the pacemaker potential. In latent atrial pacemakers, the pacemaker potential exhibits two distinct phases; an initial steep slope (D1) followed by a secondary, more gradual depolarization (D2) (Fig. 1Go). The fact that pacemaker activity can be altered by manipulating the slope of these two phases independently suggests that more than one mechanism contributes to the pacemaker potential. In fact, work from numerous laboratories indicates that multiple mechanisms contribute to both SA node and latent atrial pacemaker activities, including: 1) the hyperpolarization-activated inward current (If), 2) inward T-type and L-type Ca2+ currents, 3) time-dependent decay of K+ conductance, 4) INa/Ca, and 5) low background K+ conductance. The relative contribution of each current to pacemaker function is controversial.



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  		FIGURE 1. Spontaneously beating latent atrial pacemaker action potentials and the relative contribution of multiple mechanisms to the pacemaker potential. Em, membrane potential; D1, initial phase of the pacemaker potential; D2, secondary phase of the pacemaker potential; IK, decay of K+ current; If, activation of hyperpolarization-activated inward current; ICa,T, activation of T-type Ca2+ current; Ca2+ sparks, local sarcoplasmic reticulum (SR) Ca2+ release triggered by ICa,T; INa/Ca, stimulation of Na+/Ca2+ exchange current; restitution, time-dependent restoration of SR Ca2+ release.

 
In general, because of their low background K+ conductance, atrial pacemaker cells exhibit a relatively high input resistance (~1–2 G{Omega}). As a result, small changes in ionic current can exert large effects on membrane voltage. Because of a relatively positive threshold potential, the action potential upstroke of both SA node and latent atrial pacemakers results primarily from activation of L-type Ca2+ current (ICa,L). Depolarization during the action potential upstroke activates a delayed-rectifier K+ current (IK) that initiates repolarization, which in turn deactivates K+ channels. In conjunction with a sustained background inward current, the time-dependent decay of IK generates a net inward current that flows during the diastolic interval. In latent atrial pacemakers at voltages comparable to the maximum diastolic potential (–70 mV), the relatively short time constant (~200 ms) of IK decay indicates a contribution primarily during the initial phase of the pacemaker potential (Fig. 1Go). In addition to the decay of K+ conductance, repolarization to more negative voltages activates If, a hyperpolarization-activated inward current that is carried primarily by Na+ (4). In latent atrial pacemaker cells, hyperpolarization to –70 mV elicits a small If with a relatively slow time constant (~3 s) of activation. Cs+ blocks If and depresses the slope of the pacemaker potential, resulting in prolongation of the pacemaker cycle length by ~30–50% (18). The fact that Cs+ abolishes If without stopping pacemaker activity suggests that If modulates rather than initiates latent atrial pacemaker activity. Similar findings have been reported in the SA node. Clearly, other mechanisms must be operating to initiate and maintain atrial pacemaker function. This is emphasized by the fact that certain mammalian atrial pacemakers (16), as well as pacemaker cells in the amphibian sinus venosus (13), lack If. Latent atrial pacemaker cells lacking If exhibit a lower frequency of pacemaker activity than those atrial pacemakers that exhibit If (16).


   Ca2+ release from the sarcoplasmic reticulum
Top
 Introduction
 Multiple mechanisms contribute...
 Ca2+ release from the...
T-type Ca2+ current
 Na+/Ca2+ exchange current
 Low-voltage-activated diastolic...
 Structure-function relationship
 Conclusions
 References
 
In cardiac muscle, systolic Ca2+ release from the sarcoplasmic reticulum (SR) is a fundamental event in excitation-contraction (E-C) coupling. However, several laboratories, including our own, have reported that inhibition of SR Ca2+ release inhibits atrial pacemaker activity (8, 10, 12, 19). In latent atrial pacemakers, inhibition of SR Ca2+ release by ryanodine specifically decreases the slope of the secondary, late phase of the pacemaker potential, markedly prolonging the pacemaker cycle length (+170%). Addition of Cs+ to block If in the presence of ryanodine causes a further prolongation in pacemaker cycle length primarily by decreasing the initial phase of the pacemaker potential. The inhibitory effects of ryanodine on pacemaker cycle length are significantly more pronounced in latent atrial than SA node pacemakers and more pronounced than inhibition of If by Cs+. These results suggest that diastolic SR Ca2+ release 1) contributes to both SA node and latent atrial pacemaker activities, 2) makes a greater contribution to latent than to SA node pacemaker function, and 3) is a more significant determinant of latent atrial pacemaker activity than is If.


   T-type Ca2+ current
Top
 Introduction
 Multiple mechanisms contribute...
 Ca2+ release from the...
 T-type Ca2+ current
Na+/Ca2+ exchange current
 Low-voltage-activated diastolic...
 Structure-function relationship
 Conclusions
 References
 
An important development in our understanding of cardiac pacemaker mechanisms was the discovery that cardiac cells exhibit two inward Ca2+ currents: the relatively large, high-voltage-threshold ICa,L and a smaller, low-voltage-threshold T-type Ca2+ current (ICa,T) (1). L- and T-type Ca2+ channels can be distinguished by their steady-state voltage characteristics as well as their pharmacological properties. The molecular basis of the T-type Ca2+ channel has now been elucidated, and the channel has been cloned (3). Importantly, ICa,T is several times larger in pacemaker than nonpacemaker cardiac cells. ICa,T density is about fivefold higher in latent atrial pacemaker cells than in nonpacemaker atrial myocytes (20). Compared with ICa,L, ICa,T is little affected by the L-type Ca2+ channel blocking agents verapamil or nifedipine, but it is inhibited by low micromolar concentrations of Ni2+. In latent atrial pacemakers, 40 µM Ni2+ inhibits ICa,T, decreases the slope of the pacemaker potential, and prolongs pacemaker cell length. It is important to note that Ni2+ primarily inhibits pacemaker activity by depressing the late phase of the pacemaker potential, the same phase inhibited by ryanodine. Experiments in both SA node and latent atrial pacemakers have led to the conclusion that an ICa,T window current contributes to pacemaker activity, primarily during the secondary, late phase of the pacemaker potential (5, 20). The contribution of ICa,T is thought to result from the depolarizing effects of inward Ca2+ current. However, in cardiac Purkinje cells (17) and ventricular myocytes (14), ICa,T is capable of triggering SR Ca2+ release, although less effectively than ICa,L. Both of these studies concluded that ICa,T plays a minor role in normal E-C coupling. However, the importance of these findings may be their relevance to cardiac pacemaker function. Thus in atrial pacemaker cells both the Ni2+-sensitive ICa,T and ryanodine-sensitive SR Ca2+ release contribute to the same secondary, late phase of the pacemaker potential. Moreover, as mentioned earlier, pacemaker cells exhibit a higher density of T-type Ca2+ channels than nonpacemaker cardiomyocytes. Together these findings suggest that, in atrial pacemaker cells, voltage-dependent activation of ICa,T may trigger diastolic release of SR Ca2+. Evidence for this idea will be presented below.


   Na+/Ca2+ exchange current
Top
 Introduction
 Multiple mechanisms contribute...
 Ca2+ release from the...
 T-type Ca2+ current
 Na+/Ca2+ exchange current
Low-voltage-activated diastolic...
 Structure-function relationship
 Conclusions
 References
 
In general, Na+/Ca2+ exchange functions to maintain intracellular Ca2+ homeostasis by extruding intracellular Ca2+ in exchange for Na+ influx. Because of its stoichiometry (Na+:Ca2+ = 3:1), elevation of intracellular Ca2+ can stimulate Na+/Ca2+ exchange to generate a net inward Na+ current. Under a variety of abnormal conditions, overload of SR Ca2+ can elicit spontaneous release of SR Ca2+, resulting in transient inward current, and triggered pacemaker activities thought to result from stimulation of INa/Ca. Under normal conditions, however, the contribution of Na+/Ca2+ exchange to cardiac pacemaker activity is not entirely clear. In SA node preparations, Na+/Ca2+ exchange stimulated by SR Ca2+ release may contribute a secondary inward current. In single pacemaker cells isolated from toad sinus venosus diastolic intracellular Ca2+ concentration shows a close association with pacemaker firing rate, leading to the conclusion that Na+/Ca2+ exchange contributes to pacemaker activity in that species (8). Our laboratory has used voltage clamp methods to record diastolic currents from spontaneously active latent atrial pacemaker cells (19). Inhibition of SR Ca2+ release by ryanodine elicited a concomitant inhibition of the inward current, the diastolic slope of the pacemaker potential, and pacemaker rate (Fig. 2, A and BGo). Clamping the membrane voltage at –50 mV during the late phase of the pacemaker potential elicited a ryanodine-sensitive slow inward current (Fig. 2, C and DGo). Moreover, ß-adrenergic receptor stimulation with isoproterenol increased the inward current amplitude, diastolic slope, and pacemaker rate (Fig. 2, E–GGo). Ryanodine inhibited each of these effects of isoproterenol. These findings are consistent with the idea that SR Ca2+ release during the late diastolic interval stimulates inward INa/Ca, thereby depolarizing the pacemaker potential toward threshold. Moreover, stimulation of SR Ca2+ release contributes significantly to the positive chronotropic effects of ß-adrenergic receptor stimulation. Similar conclusions have been reported in guinea pig atria (see Ref. 15 for references) and toad sinus venosus (8).



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  		FIGURE 2. The role of SR Ca2+ release and INa/Ca in latent atrial pacemaker activity (19). Compared with control (A), exposure to 1 µM ryanodine (B) decreased pacemaker rate and the slope of the pacemaker potential. In control (C), voltage clamping the late pacemaker potential at –50 mV elicited a transient inward current that decayed to a background net inward current. Ryanodine (D) abolished the inward currents and decreased the slope of the pacemaker potential. Compared with control (E), 500 nM isoproterenol (Iso; F) significantly increased inward currents and the slope of the pacemaker potential. Addition of ryanodine (Rya; G) inhibited the isoproterenol-stimulated inward currents and decreased the slope of the pacemaker potential.

 

   Low-voltage-activated diastolic Ca2+ sparks
Top
 Introduction
 Multiple mechanisms contribute...
 Ca2+ release from the...
 T-type Ca2+ current
 Na+/Ca2+ exchange current
 Low-voltage-activated diastolic...
Structure-function relationship
 Conclusions
 References
 
As mentioned earlier, several laboratories, including our own, have reported that diastolic SR Ca2+ release plays a role in atrial pacemaker function. Recent work from our laboratory has used confocal microscopy and Ca2+-sensitive fluorescent indicators to directly measure SR Ca2+ release during the pacemaker potential (6). In contrast to ventricular muscle, atrial cells generally lack a transverse tubule (T-tubule) system. As a result, E-C coupling is initiated by Ca2+-induced Ca2+ release from SR that are in close proximity to the subsarcolemmal surface membrane (7). We therefore used high resolution confocal imaging of the subsarcolemmal space to measure local changes in subsarcolemmal intracellular Ca2+ concentration ([Ca2+]ss). Simultaneous measurements of pacemaker action potentials (Fig. 3AGo) and [Ca2+]ss (Fig. 3BGo) recorded from a spontaneously beating latent atrial pacemaker cell showed that each pacemaker action potential coincided with a rapid rise of [Ca2+]ss due to SR Ca2+ release triggered by Ca2+ entry through voltage-gated Ca2+ channels. Ca2+ release occurred almost simultaneously throughout the subsarcolemmal space during the action potential. No change in [Ca2+]ss was observed immediately following repolarization. However, [Ca2+]ss gradually increased during the late phase of the pacemaker depolarization before the action potential, resulting in a small increase in diastolic Ca2+ in recordings averaged over the subsarcolemmal space. Recordings of [Ca2+]ss from restricted regions (~1 µm) close to an active release site (Fig. 3CGo) revealed that the increase in [Ca2+]ss was caused by the summation of individual local Ca2+ release events, i.e., Ca2+ sparks. The surface plot (Fig. 3DGo) demonstrates the absence of Ca2+ sparks during early diastolic depolarization immediately following the prior pacemaker action potential and a gradual increase in Ca2+ spark frequency during the late pacemaker depolarization. In this cell, the increase in diastolic [Ca2+]ss became detectable with the occurrence of the first subsarcolemmal Ca2+ spark at a membrane potential of –58 mV.



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  		FIGURE 3. Diastolic SR Ca2+ release during the late phase of the pacemaker potential (6). Simultaneous recordings of membrane voltage (Vm; A) and subsarcolemmal Ca2+ concentration ([Ca2+]ss; B) are shown. The lower traces in each panel show amplified recordings of diastolic voltage (A) and [Ca2+]ss (B). [Ca2+]ss increases during the late phase of the pacemaker potential (B). The increase in [Ca2+]ss shown in C was due to local Ca2+ release events, i.e., Ca2+ sparks (arrows). Increase in [Ca2+]ss during the pacemaker potential that precedes an action potential is shown in D. Position of the line scan on the cell is shown in D, inset.

 
Further experiments showed that diastolic Ca2+ release is triggered by a voltage-dependent mechanism. For these experiments, we used a ramp/step voltage clamp protocol to simulate the pacemaker potential and action potential, respectively. The ramp depolarization (–70 to –40 mV) elicited a small increase in intracellular Ca2+ that preceded the [Ca2+]ss transient triggered by the step-induced (–40 to 0 mV) activation of ICa,L. The diastolic increase in Ca2+ was initiated at –57 mV. This low-voltage-activated Ca2+ release seen under voltage clamp conditions mimicked the increase in diastolic Ca2+ recorded from spontaneously beating pacemaker cells. Like the diastolic increase in intracellular Ca2+ in spontaneous cells, the low-voltage-activated Ca2+ release resulted from the summation of individual subsarcolemmal Ca2+ sparks. When the ramp depolarization was omitted and membrane voltage was held constant (–70 mV) before the voltage step, diastolic Ca2+ release was not observed. These findings indicate that Ca2+ release during the ramp depolarization and therefore during the late phase of the pacemaker potential is dependent on membrane depolarization rather than due to some sort of spontaneous, time-dependent SR Ca2+ release mechanism. The voltage threshold of –57 mV excludes activation of L-type Ca2+ channels but is compatible with Ca2+-induced Ca2+ release induced by Ca2+ entry through low-voltage-activated T-type Ca2+ channels.

As mentioned earlier, micromolar concentrations of Ni2+ block cardiac ICa,T channels, decrease the late slope of pacemaker potential, and inhibit pacemaker rate. Similarly, in these experiments Ni2+ (25–50 µM) prolonged spontaneous cycle length by 230% compared with control and suppressed the diastolic increase in intracellular Ca2+. Under voltage clamp conditions, Ni2+ also inhibited low-voltage-activated Ca2+ release at voltages negative to –45 mV but was without effect on Ca2+ release triggered by ICa,L at voltages positive to –45 mV. In addition, latent atrial pacemaker cells exhibited a slow inward current that coincided with the diastolic increase in intracellular Ca2+, suggesting that the current was due to stimulation of INa/Ca. A similar Ca2+ release-dependent current that develops during the late phase of the pacemaker potential was previously identified in these cells as INa/Ca (19). The fact the low-voltage-activated SR Ca2+ release occurs primarily during the late phase of the pacemaker potential also appears to be related to a time-dependent restitution of SR Ca2+ release during diastole (Fig. 1Go). Indeed, in latent atrial pacemaker cells SR Ca2+ release becomes increasingly available over time that is compatible with the pacemaker cycle length (19). This probably is due to dynamic time-dependent processes, such as reuptake of SR Ca2+ and recovery of Ca2+ release channels, that occur during the diastolic interval between beats.

Further experiments (6) indicate that nonpacemaker atrial myocytes completely lack low-voltage-activated Ca2+ release when stimulated with a ramp/step protocol. However, in single SA node pacemaker cells isolated from the same cat hearts a small, low-voltage-activated Ca2+ release was detected at a threshold voltage of –55 mV. This finding is consistent with the effect of ryanodine to inhibit SA node pacemaker activity. It therefore appears that low-voltage-activated Ca2+ release is specific for pacemaker cells and is not found in regular atrial muscle cells. This is consistent with the higher density of T-type Ca2+ channels in pacemaker cells compared with nonpacemaker atrial myocytes.


   Structure-function relationship
Top
 Introduction
 Multiple mechanisms contribute...
 Ca2+ release from the...
 T-type Ca2+ current
 Na+/Ca2+ exchange current
 Low-voltage-activated diastolic...
 Structure-function relationship
Conclusions
 References
 
The present findings indicate that Ca2+ release from the SR plays an important functional role in atrial pacemaker activity. Atrial pacemaker cells do not contain T-tubules, and therefore the subsarcolemmal SR cisternae are located along the cell periphery. Latent atrial pacemaker cells exhibit morphological and ultrastructural features similar, though not identical, to pacemaker cells (P cells) located in the SA node region (11, 18). Both types of pacemaker cells are relatively small in diameter (5–7 µm) and exhibit tapered ends, sparse, randomly oriented myofibrillar material, and numerous mitochondria. The main distinguishing characteristic is the unique architecture of subsarcolemmal SR cisternae in latent atrial pacemaker cells. As shown in Fig. 4Go, electron micrographs of latent atrial pacemaker cells show prominent subsarcolemmal SR cisternae that are directly apposed to one another between two adjacent cells. This structure is not seen in SA node tissue from the same hearts. Between each subsarcolemmal SR cistern and the cell membrane is diffuse, electron-dense material that corresponds to the "feet" structures or ryanodine receptors. Moreover, along the region of SR apposition, the two cell membranes invariably come together at a distance of ~25 nm. This distance is similar to the subsarcolemmal space located between the surface membrane and the nearest margin of SR membrane (20–22 nm), which is generally considered to be a restricted space. How this unique SR architecture is relevant to latent atrial pacemaker activity is not clear. However, as shown in the schematic diagram (Fig. 4BGo), we speculate that this region may represent a modified form of a T-tubule-SR complex or triad commonly seen in ventricular muscle. Because these pacemaker cells contain relatively little myofibrillar material, it seems unlikely that this structure is relevant to E-C coupling. However, like T-tubules, Ca2+ channels (in this case T-type) and Na+/Ca2+ exchangers may be colocalized and more concentrated within this region. A higher density of T-type Ca2+ channels would result in a more efficient trigger for diastolic SR Ca2+ release, and a higher density of Na+/Ca2+ exchangers would provide a more effective means of developing net inward current. Moreover, a restricted extracellular space at the apposed SR region may indicate as yet unknown mechanisms by which pacemaker cells communicate to facilitate SR Ca2+ release. When latent atrial pacemakers function as dominant pacemakers, the functional properties resulting from this unique architecture may increase the margin of safety for generating coordinated pacemaker activity among groups of pacemaker cells.



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  		FIGURE 4. Electron micrograph (A) and schematic drawing (B) showing the architecture of SR cisternae in latent atrial pacemaker cells. The photomicrograph shows that subsarcolemmal SR cisternae are prominent and directly apposed to one another in 2 adjacent pacemaker cells. Bar = 0.25 µm. The schematic drawing shows our hypothesis that Ca2+ influx via T-type Ca2+ channels triggers diastolic SR Ca2+ release, which in turn stimulates Na+/Ca2+ exchange to generate net inward Na+ current. We speculate that within the region of the apposed SR cisternae T-type Ca2+ channels and Na+/Ca2+ exchangers are colocalized and their density is relatively high.

 

   Conclusions
Top
 Introduction
 Multiple mechanisms contribute...
 Ca2+ release from the...
 T-type Ca2+ current
 Na+/Ca2+ exchange current
 Low-voltage-activated diastolic...
 Structure-function relationship
 Conclusions
References
 
Multiple mechanisms contribute to atrial pacemaker activity (Fig. 1Go). The present work demonstrates a novel pacemaker mechanism in which voltage-dependent activation of ICa,T triggers diastolic SR Ca2+ release, which in turn stimulates inward INa/Ca to depolarize the late phase of the pacemaker potential toward threshold. Depolarization during the late pacemaker potential is expected to elicit further activation of ICa,T, resulting in a positive feedback. This mechanism suggests that ICa,T serves a dual function during the pacemaker potential: 1) to carry a small inward Ca2+ current and 2) to trigger release of SR Ca2+. The latter Ca2+-induced Ca2+ release mechanism, typically associated with E-C coupling, is expected to amplify and temporally integrate the depolarizing effects of T-type Ca2+ channel activation by stimulating a larger secondary inward INa/Ca during the pacemaker potential. On the basis of this mechanism, interventions that alter SR Ca2+ content and/or release are expected to regulate atrial pacemaker activity. In fact, stimulation of SR Ca2+ uptake and release appears to underlie ß-adrenergic receptor stimulation of latent atrial pacemaker activity. In this scenario, ICa,L acts primarily to regulate Ca2+ influx and fill SR Ca2+ stores. In relation to abnormal pacemaker function, drugs or disease processes that elevate SR Ca2+ may act via low-voltage-activated SR Ca2+ release to abnormally enhance atrial pacemaker automaticity. Abnormal pacemaker activity may therefore arise from Ca2+-mediated mechanisms that need not invoke delayed afterdepolarizations and triggered activity, which require spontaneous diastolic Ca2+ release from an SR overloaded with Ca2+. Because latent atrial pacemakers are more dependent on low-voltage-activated SR Ca2+ release than primary pacemakers, they may be more susceptible to Ca2+-mediated dysrhythmic activities. Moreover, diastolic SR Ca2+ release may play a more important role in generating activity in pacemaker cells lacking If. An understanding of the different mechanisms underlying atrial pacemaker activity may provide insight into the etiology and ultimate prevention of certain types of atrial arrhythmias.


   References
Top
 Introduction
 Multiple mechanisms contribute...
 Ca2+ release from the...
 T-type Ca2+ current
 Na+/Ca2+ exchange current
 Low-voltage-activated diastolic...
 Structure-function relationship
 Conclusions
 References
 

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