Calcium‐activated potassium current: parallels in cardiac development and disease

The shape of the action potential is tightly controlled in healthy cardiac myocytes. In adult ventricular cells, the upstroke of the action potential is triggered by the opening of Na+ channels, which in turn triggers the opening of voltage-gated Ca2+ and K+ channels. This sequential channel opening fine-tunes the magnitude and kinetics of Ca2+ current and thus its ability to trigger sarcoplasmic reticulum (SR) Ca2+ release and contraction. Furthermore, the depolarizing and hyperpolarizing currents are delicately balanced to ensure electrical stability, with a minimized risk of triggered extra beats (extra-systoles). By regulating Ca2+ homoeostasis, action potential configuration also contributes to the control of Ca2+-dependent gene regulation in diverse cell processes ranging from metabolism to cell growth. Perhaps not surprisingly, the configuration of the action potential in the developing heart is considerably different than in the adult, but well suited to the heart's demands at each developmental stage. In the early embryo, from approx. embryonic day 8 in mice, immature cardiomyocytes exhibit rhythmic beating activity due to spontaneous release of Ca2+ from the SR, via ryanodine receptors and IP3 receptors (Louch et al. 2015). Removal of this released Ca2+ by the Na+-Ca2+ exchanger results in a depolarizing current, which then activates Na+ and Ca2+ currents, giving rise to action potentials and contraction. In this issue of Acta Physiologica, Karppinen et al. (2015) have discovered that Ca2+-activated K+ current (IK(Ca)) is also a critical regulator of embryonic pacemaking and action potential configuration. Their results show that the small-conductance K+ (SK) channels SK2 and SK3 are expressed in embryonic heart and that their function is blocked by the SK channel inhibitor apamin. As in other cell types, the outward IK(Ca) is activated by moderate intracellular [Ca2+] and promotes hyperpolarization of the resting membrane potential (see Figure 1 Panel a). This hyperpolarization appears to promote spontaneous cell beating, that is oscillations of cytosolic [Ca2+], in embryonic cells by reducing inactivation of voltage-gated Na+ and Ca2+ currents. The authors theorize that the larger L-type Ca2+ current in turn increases SR Ca2+ content, making spontaneous Ca2+ release more frequent. Hyperpolarization by IK(Ca) would also be expected to drive greater recruitment of the depolarizing funny current, If, which further stabilizes pacemaking. Interestingly, regular IK(Ca)-dependent beating of embryonic cells is shown to be a requirement for activation of Ca2+-regulated genes, such as those in the NFAT pathway, and for normal morphological development. Based on these observations in embryonic cells, it is perhaps not surprising that SK channel activity is also reported to promote differentiation of pluripotent stem cells towards the cardiac lineage (Kleger et al. 2010). Such differentiation includes cytoskeletal organization and inhibition of proliferation, with preferential differentiation towards beating cardiomyocytes reminiscent of those in the sinoatrial node (Kleger et al. 2010). Indeed, SK channels appear to retain an important role in sinoatrial pacemaking into adulthood. Analogous to present observations in embryonic cardiac cells, Chen et al. (2013) reported that inhibition of IK(Ca) by apamin significantly reduced spontaneous activity in adult nodal cells. The authors attributed these effects to prolongation of action potential duration by apamin, which would be expected to lengthen the effective refractory period for reactivation. However, a modest depolarization was also observed, which the findings of Karppinen et al. (2015) suggest might reduce SR Ca2+ stores, and thus pacing frequency. SK channels may therefore play parallel roles for pacemaking in embryonic cells, differentiating cardiac stem cells, and adult sinoatrial nodal cells. Notably, SK channels are involved in a variety of cellular functions and differentiation events during embryogenesis, in a large number of cell and tissue types. Although SK channels are expressed in adult ventricular cardiomyocytes, at least at low levels, it appears that IK(Ca) is not robustly present (Zhang et al. 2015). However, accumulating data suggest that there is an increased role of SK channels during disease. The results of Karpinnen et al. indicate that this shift marks a revisitation of the embryonic/foetal phenotype, a common phenomenon in disease as adult genes are repressed and foetal genes re-expressed. In conditions such as heart failure, previous work has shown that the return to an immature phenotype includes loss of t-tubules and dyadic structure, reduced expression of SERCA, ryanodine receptors, and L-type Ca2+ channels, and greater expression of T-type Ca2+ channels and Na+-Ca2+ exchanger (reviewed in (Louch et al. 2015). In failing ventricular cells, the reappearance of IK(Ca) has been documented in both animal models and humans and appears to reflect both a re-expression of SK channels and greater channel activation due to disrupted Ca2+ homoeostasis in this condition (Zhang et al. 2015). IK(Ca) acts to shorten the action potential in failing cells (Chua et al. 2011), and a resulting decrease in effective refractory period may predispose myocardium to re-entrant arrhythmia (see Figure 1 Panel b). Indeed, blockade of IK(Ca) by apamin has been shown to inhibit ventricular fibrillation in animal models (Chua et al. 2011). In contrast, apamin-induced action potential prolongation is reported to increase the risk of early afterdepolarizations during heart failure (Panel b). These findings reiterate the fine balance required to maintain cardiomyocyte electrical stability and suggest that possible therapeutic modulation of SK channels during heart failure should be conducted with caution. IK(Ca) is considerably more prominent in the adult atrium than it is in the ventricle, and both SK channel expression and IK(Ca) are markedly increased during atrial fibrillation. As in heart failure, the increased prominence of this hyperpolarizing current in animal models and atrial fibrillation patients shortens refractory period and increases susceptibility to tachycardia (reviewed in Zhang et al. 2015). Shortened refractory period and increased atrial fibrillation vulnerability have also been reproduced by overexpression of the SK3 channel. SK2 channel ablation, on the other hand, was observed to prolong action potentials and increase the rise of early afterdepolarizations and atrial fibrillation (Zhang et al. 2015). Thus, as in the ventricles, both abbreviation and prolongation of action potentials by IK(Ca) modulation can be pro-arrhythmic depending on the precise disease context. It is worth considering that prominence of SK channels in developing and diseased hearts may indicate similar conditions which signal their recruitment. Elevated cytosolic [Ca2+], as expected during atrial fibrillation and heart failure, has been suggested to increase expression of SK2 channels and their trafficking to membrane (Zhang et al. 2015). It is unknown whether Ca2+ is elevated in developing cells, but it seems likely based on slow rates of Ca2+ extrusion and SR re-uptake (Louch et al. 2015). Karppinen et al. (2015) show that IK(Ca) is involved with recruitment of Ca2+-dependent genes such as the NFAT signalling pathway in embryonic cells. While NFAT signalling is an established, central trigger of pathological hypertrophy, the involvement of SK channels in the regulation of this pathway during disease remains surprisingly underinvestigated. However, L-type Ca2+ current has been shown to trigger pathological NFAT activation (Gao et al. 2012), and SK channels are physically coupled with L-type channels via α-actinin2 (Zhang et al. 2015). Thus, a complex interplay between these channels may be envisioned; by fine-tuning membrane repolarization and L-type Ca2+ current, SK channels could modulate Ca2+-dependent hypertrophy, while local Ca2+ levels near the L-type channel may in turn control SK channel expression and activity. Teasing out the details of this complex relationship will certainly be challenging, but we suggest that insight can be gained by comparing observations in developing and diseased hearts. We declare no conflict of interest.