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The transient elevation of intracellular Ca2+ ([Ca2+]i) with each heartbeat underlies the activation of contraction and contributes to diverse regulatory features of cellular and subcellular behavior. Clear differences in the details of Ca2+ signaling occur in different cardiac tissues and vary in the same tissue from species to species. For example, Ca2+ sparks, the elementary unit of Ca2+ signaling in heart myocytes [1, 2] are plentiful during quiescent (diastolic) periods in ventricular myocytes from small rodents (e.g. rats and mice) but are rare in rabbits, dogs and humans. There are also important structural and cellular signaling differences in ventricular versus atrial myocytes. We now draw attention to the findings reported in this issue of the Journal of Molecular and Cellular Cardiology by Walden et al. (2009) who have examined the differences in Ca2+ signaling and in the levels of sarcoplasmic reticulum (SR) Ca2+ cycling proteins in atrial and ventricular myocytes . They report the unexpected finding in rat heart that while the [Ca2+]i transient in atrial myocytes is much smaller than in ventricular myocytes, the Ca2+ uptake mechanism is more robust and abundant and the SR Ca2+ content is greater. This may be due to the higher level of expression of sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) in atrial myocytes. This finding is surprising because the higher SR Ca2+ content might be expected to lead to Ca2+ overload. While such SR Ca2+ overload would promote arrhythmogenesis in ventricular myocytes, this is not a prominent feature of healthy atrial tissue. Here we discuss these findings and put them in context with normal and diseased atrial Ca2+ signaling.
Atrial myocytes are thinner and have fewer transverse tubules (TTs) than do their ventricular counterparts [4, 5]. They also possess smaller cell surface area and cell volume . These prominent anatomic differences contribute to the unique Ca2+ signaling phenotype observed in healthy atrial myocytes . Triggered Ca2+ sparks are produced at junctional SR (jSR) couplings at the surface and at jSR-TT sites. The triggering is initiated by the cellular depolarization during the cardiac action potential (AP) due to the openings of L-type Ca2+ channels (LTCCs). The local Ca2+ influx through LTCCs increases [Ca2+]i in the “subspace” (the approximately 15 nm wide space between the surface sarcolemmal or TT membrane and the jSR membrane) and the elevated [Ca2+]subspace activates the SR Ca2+ release channels (ryanodine receptors or RyR2s) in the jSR. RyR2s are organized into a paracrystalline array (or cluster of RyR2s). This local amplification of the LTCC signal is due to “Ca2+-induced Ca2+ release” or CICR and activates a Ca2+ spark at the jSR. During the AP, almost all Ca2+ sparks in ventricular myocytes are activated directly by LTCCs and thus synchronized to produce the rising phase of the [Ca2+]i transient. In atrial myocytes the process is somewhat different. The [Ca2+]i transient begins with the LTCC-triggered local SR Ca2+ release events (i.e. Ca2+ sparks) where the anatomy permits. The [Ca2+]i transient continues as the Ca2+ release events are activated at other RyR2 cluster sites by CICR. The line-scan images of such slowly propagating CICR reveals a clear delay of the [Ca2+]i transient deep in the atrial myocyte and the exact shape of the propagating signal depends on the extent of TT development in the atrial myocytes that are examined. The more TTs, the more rapid the deep [Ca2+]i transient occurs. In ventricular myocytes no propagation delay in Ca2+ signal is observed . Since isolated Ca2+ sparks in ventricular myocytes do not produce a propagating CICR signal under normal conditions, we and others had wondered what enabled such triggered Ca2+ sparks in atrial myocytes to produce the relatively slowly propagating Ca2+ signal that is normal in that tissue . The findings of Walden et al. (2009) suggest that one critical factor may be the relatively elevated SR [Ca2+] content in atrial versus ventricular myocytes.
While Walden et al. (2009) indicate important differences in atrial Ca2+-handling proteins from those in ventricular myocytes, some of these differences also may contribute to or underlie abnormal Ca2+ signals in atrial myocytes in disease states (see above and below). Accumulating evidence supports the observations of Walden et al. (2009) and suggest that there are substantial differences in expression and function of Ca2+-handling proteins in atria compared to ventricles [9–12]. Muscle contraction and relaxation times and [Ca2+]i-transient durations are shorter in atrial versus ventricular tissue of different species [12–14]. In the atria, protein levels [10, 12] and activity [10, 12, 15] of SERCA2a are more than 2-fold higher, whereas SERCA2a-inhibitory protein phospholamban (PLN) is less expressed [10, 12]. Atrial myocytes also express sarcolipin (SLN), an additional SERCA2a-inhibitory protein, that, when knocked out, enhances atrial SR Ca2+ uptake and contractility . Atrial protein levels of RyR2  and its regulators calsequestrin, triadin and junctin as well as of NCX1  are lower than ventricular .
As [Ca2+]SR increases, the sensitivity of RyR2s to triggering by cytosolic [Ca2+]i increases . This also means that one Ca2+ spark is more likely to trigger another Ca2+ spark in atrial myocytes and remain a rare event in normal ventricular myocytes. To the extent that the SR has elevated [Ca2+]SR, there is a more rapid propagation of the [Ca2+]i transient deep in the atrial myocyte via CICR even in the absence of TTs. Under normal circumstances, this may be an adaptive mechanism that supports normal EC coupling in atrial myocytes. The thin (small diameter) character of atrial myocytes suggests that the length of propagation by CICR across the radius of the atrial myocyte is relatively small and this small distance should provide signal stability. It is, in fact, a “firewall” against runaway Ca2+ instability. Kirk et al. (2003) noted that in the rat, bigger atrial myocytes did tend to have more TTs and also axial components of these invaginations, identified as an ensemble called the Transverse Axial Tubule System (TATS) . Thus the increase in the number of TATS elements would lessen the distance involved in the slow propagation of CICR that is generally observed in atrial myocytes. However, the benefit of the elevation of the SR Ca2+ content discovered by Walden et al. (2009) is that it should improve synchrony of the atrial [Ca2+]i transient when TTs are absent or sparse. The disadvantage of such an elevated SR Ca2+ content and enhanced [Ca2+]SR is the increased sensitivity of the CICR process. For thin cells or large diameter cells with many invaginations in the TATS, the Ca2+ signal propagation is likely to be relatively stabile. Large myocytes without elements of the TATS (see Fig. 1), however, will have an increased proclivity towards subcellular Ca2+ alternans. Since uncontrolled subcellular or cellular [Ca2+]i elevations, as occurs with Ca2+ alternans [19–21], will activate the Na/Ca exchanger and thereby generate Na/Ca exchanger current (INCX) between APs with subsequent induction of delayed after depolarizations, the high SR Ca2+ content in atrial myocytes may be proarrhythmic. Such arrhythmogenic tendencies may be unmasked as cells hypertrophy and/or as elements of the TATS diminish (see Fig. 2). Additional experimental investigations and mathematical modeling should be carried out to test this hypothesis.
The work by Walden et al. (2009) and others suggest that important differences in subcellular and global [Ca2+]i signaling exist between atrial and ventricular myocytes. The greater SR Ca2+ content in atrial cells while “pro-arrhythmic” in principle obviously does guarantee relatively rapid [Ca2+]i signaling when TTs are sparse. If, however, pathological conditions develop that increase the size of the atrial cells without TATS members (see Fig. 1A and 1B in contrast to 1C), decrease the abundance of TTs in large atrial myocytes or further increase atrial Ca2+ overload, it is possible that cellular and subcellular Ca2+ instability develops (see Fig. 2). It is also possible that an even higher SR Ca2+ content becomes an important contributor to atrial arrhythmogenesis [4, 22]. Abnormal Ca2+ signaling may thus underlie or contribute to a variety of cellular processes known to be key in atrial arrhythmogenesis (see Figure 2B). For instance, atrial SR Ca2+ load further increases in dogs with experimental heart failure and likely contributes to both re-entry and triggered activity that underlie heart failure-induced AF . During AF-related Ca2+-overload conditions in vivo, reduced inhibition of SERCA2a by phosphorylated PLN  helps to maintain a normal SR Ca2+ load in patients with AF despite the possibly increased frequencies of Ca2+ sparks and waves through potentially leaky (hyperphosphorylated) RyR2 channels [25, 26]. Increased spontaneous Ca2+ releases and Ca2+ waves, however, may induce delayed after depolarizations and triggered activity that may contribute to AF maintenance. In addition to complex conduction disturbances and reentry, Ca2+-dependent focal sources at the cellular and subcellular levels may contribute importantly to AF pathogenesis. Full and direct experimental investigations of the relationships between local Ca2+-release events, cellular Ca2+ dysfunction and AF, however, is still lacking. High-resolution optical mapping investigations that may discriminate between re-entry and focal activity are challenging and needed.
In conclusion, Walden et al. (2009) have carefully compared atrial to ventricular myocytes in rat heart providing important novel insights of atrial Ca2+ signaling. Their findings support enhanced SR Ca2+ content and likely increased Ca2+-induced Ca2+ release in normal atrial myocytes. Finally these findings are consistent with the hypothesis that this increase in SR Ca2+ content may play an important role in the Ca2+-signaling dysfunction that contributes to the pathogenesis of AF.
The authors research is supported by the German Research Foundation (DFG, DOB 769/1-3 to D.D.), German Federal Ministry of Education and Research (Atrial Fibrillation Competence Network grant 01Gi0204, projects C3 and C4 to D.D.), a network-grant from Fondation Leducq (07 CVD 03, “European North American Atrial Fibrillation Research Alliance”, to D.D. and W.J.L.), a Interdisciplinary Training Program Muscle Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases (to L.T.), and by the National Heart Lung & Blood Institute(to W.J.L.).