Sex‐specific density of ventricular SK currents: is this a general feature of SK channel function?

Small-conductance Ca2+-activated K+ channels (SK channels) contribute to cardiac repolarization, thereby shaping the characteristic form of the cardiac action potential (AP). Under physiological conditions, functional SK channels are predominantly active in cells of the sinus node and atrioventricular node, in atrial cardiomyocytes, and in Purkinje fibre cells, where they participate in repolarization and perhaps stabilization of the atrial resting membrane potential. Calcium handling is markedly perturbed in atrial fibrillation (AF) patients, and as a consequence, the SK channels are additionally activated, contributing to AF-related AP duration (APD) shortening and triggered activity (Heijman & Dobrev, 2017). Although the possible anti-fibrillatory effect of SK-channel block has been demonstrated in several models of AF, the therapeutic value of SK channel block has to date not been proven in the clinical setting (Diness et al. 2015). In ventricular cardiomyocytes, SK channel abundance is relatively low, but upregulation is typical for failing ventricular cardiomyocytes. This upregulated SK channel activity causes shortening of the ventricular AP, which in turn promotes recurrent ventricular fibrillation, presumably by promoting late phase 3 early afterdeplarisations and reentry (Chua et al. 2011). The factors contributing to the low activity of SK channels in the ventricle are poorly understood. As reported in this issue of The Journal of Physiology, Chen et al. (2018) studied sex-specific SK channel activation in the ventricle, particularly in settings mimicking increased sympathetic drive, which accompanies many pathophysiological conditions and the physiological ‘fight-or-flight’ response. In ventricular cardiomyocytes from both male and female rabbits, the highly selective SK channel blocker apamin caused only a small prolongation of the AP under basal conditions. In the presence of β-adrenoceptor stimulation, by contrast, apamin significantly prolonged the AP, particularly in cardiomyocytes from female rabbits. Here, moreover, isoprenaline caused a potentially proarrhythmic AP triangulation, which was reversed by apamin. The authors discovered that SK current density was higher in ventricular cardiomyocytes from females compared to male rabbits. The protein levels of the major cardiac channel subunit SK2 were also greater in females versus males, and were associated will a lower abundance of the SK channel inhibitory casein kinase-2 (CK2). The latter should result in a relative CK2 deficiency and a stronger SK2 channel subunit dephosphorylation, conceivably increasing Ca2+ sensitivity and thus activity of SK channels. This may potentially explain the observed sex-specific differences in SK channel function. Finally, SK channel activation was associated with discordant phase 2 repolarization alternans and facilitation of ventricular fibrillation, which were both eliminated with apamin in females only. These data imply an important contribution of SK channels to ventricular arrhythmogenesis in females during adrenergic stress, and suggest that inhibition of SK channels might allow tailored antiarrhythmic therapy in females. The work by Chen et al. extends previous knowledge about differences in ion channel function and related electrocardiographic features between males and females by demonstrating a sex-specific contribution of SK channels to cardiac electrophysiology. This study also raises several important questions. The current data point to CK2 deficiency (hence lower SK channel subunit phosphorylation, and increased Ca2+ sensitivity and channel activity) as one potential mechanism of augmented SK channel function in females. However, numerous other potential mechanisms also require consideration. Differences in counterregulatory (stimulatory) type 2a protein phosphatase activity, mechanisms and degree of channel subunit trafficking, and abundance of Ca2+-sensing calmodulin to the channel subunits might all contribute to the sex-specific differences and should be assessed specifically in future studies (Heijman & Dobrev, 2017). In the normal heart, β-adrenoceptor-mediated activation of SK channels occurs in a sex-specific manner, but it remains to be shown if the diseased ventricle responds in a similar way. Also, the increase in ventricular rate and the related cardiomyocyte Ca2+ overload which occur during ventricular fibrillation are expected to activate SK channels, potentially amplifying the sex-specific differences in SK channel function. Finally, it will also be of interest to check for sex-specific differences in SK channel function in atrial cardiomyocytes or cells of the sinus and atrioventricular nodes. This might offer novel therapeutic opportunities for the treatment of supraventricular rhythm disturbances. The study by Chen et al. (2018) provides clear evidence that SK channels are important contributors to the shape of the ventricular AP under conditions simulating increased sympathetic drive, and that SK channel inhibition might be a promising antiarrhythmic strategy for pharmacological treatment of ventricular fibrillation, particularly in females. Although block of SK channels may prolong ventricular AP, preventing reentrant arrhythmias, it may make the ventricular cardiomyocytes more sensitive to Ca2+-dependent triggered activity (Hsueh et al. 2013). Thus in subsequent studies it would be important to assess whether inhibition of SK channels may cause both pro- and antiarrhythmic effects in the diseased ventricle, particularly in females. Dr Dobrev is on the Scientific Advisory Board of OMEICOS Therapeutics GmbH and Acesion Pharma and received speaker's fees from Boston Scientific, Servier, and Novartis. His laboratory executed research contracts for OMEICOS. Sole author. The author's work is supported by the National Institutes of Health (R01-HL131517 and R01-136389), and the German Research Foundation (DFG, Do 769/4-1 to D.D.).