Small-conductance calcium-activated potassium channels in the heart: expression, regulation and pathological implications

Ca2+-activated K+ channels are critical to cellular Ca2+ homeostasis and excitability; they couple intracellular Ca2+ and membrane voltage change. Of these, the small, 4-14 pS, conductance SK channels include three, KCNN1-3 encoded, SK1/KCa2.1, SK2/KCa2.2 and SK3/KCa2.3, channel subtypes with characteristic, EC50 similar to 10 nM, 40 pM, 1 nM, apamin sensitivities. All SK channels, particularly SK2 channels, are expressed in atrial, ventricular and conducting system cardiomyocytes. Pharmacological and genetic modification results have suggested that SK channel block or knockout prolonged action potential durations (APDs) and effective refractory periods (ERPs) particularly in atrial, but also in ventricular, and sinoatrial, atrioventricular node and Purkinje myocytes, correspondingly affect arrhythmic tendency. Additionally, mitochondrial SK channels may decrease mitochondrial Ca2+ overload and reactive oxygen species generation. SK channels show low voltage but marked Ca2+ dependences (EC50 similar to 300-500 nM) reflecting their alpha-subunit calmodulin (CaM) binding domains, through which they may be activated by voltage-gated or ryanodine-receptor Ca2+ channel activity. SK function also depends upon complex trafficking and expression processes and associations with other ion channels or subunits from different SK subtypes. Atrial and ventricular clinical arrhythmogenesis may follow both increased or decreased SK expression through decreased or increased APD correspondingly accelerating and stabilizing re-entrant rotors or increasing incidences of triggered activity.This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

Automated summary

Ca2+-activated K+ channels play a critical role in cellular Ca2+ homeostasis and excitability by coupling intracellular Ca2+ and membrane voltage change. Among these channels, the SK channels, with small conductance and three subtypes, SK1/KCa2.1, SK2/KCa2.2, and SK3/KCa2.3, are expressed in various cardiomyocytes and show specific sensitivities to apamin. SK channels regulate action potential durations and effective refractory periods, potentially affecting arrhythmic tendency. Additionally, mitochondrial SK channels may mitigate mitochondrial Ca2+ overload and reactive oxygen species generation. SK channels exhibit low voltage but significant Ca2+ dependences, and their function relies on complex trafficking, expression processes, and associations with other ion channels or subunits from different SK subtypes. Clinical arrhythmogenesis in atrial and ventricular tissues can be influenced by altered SK expression, leading to changes in re-entrant rotors or triggered activity.