Small-conductance Ca²⁺-activated K⁺channel activation deteriorates hypoxic ventricular arrhythmias via CaMKII in cardiac hypertrophy

Abstract

The molecular and electrophysiological mechanisms of acute ischemic ventricular arrhythmias in hypertrophied hearts are not well known. We hypothesized that small-conductance Ca-activated K (SK) channels are activated during hypoxia via the Ca/calmodulin-dependent protein kinase II (CaMKII)-dependent pathway. We used normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs) as a model of cardiac hypertrophy. The inhibitory effects of SK channels and ATP-sensitive K channels on electrophysiological changes and genesis of arrhythmias during simulated global hypoxia (GH) were evaluated. Hypoxia-induced abbreviation of action potential duration (APD) occurred earlier in ventricles from SHRs versus. WKY rats. Apamin, a SK channel blocker, prevented this abbreviation in SHRs in both the early and delayed phase of GH, whereas in WKY rats only the delayed phase was prevented. In contrast, SHRs were less sensitive to glibenclamide, a ATP-sensitive K channel blocker, which inhibited the APD abbreviation in both phases of GH in WKY rats. SK channel blockers (apamin and UCL-1684) reduced the incidence of hypoxia-induced sustained ventricular arrhythmias in SHRs but not in WKY rats. Among three SK channel isoforms, SK2 channels were directly coimmunoprecipitated with CaMKII phosphorylated at Thr (p-CaMKII). We conclude that activation of SK channels leads to the APD abbreviation and sustained ventricular arrhythmias during simulated hypoxia, especially in hypertrophied hearts. This mechanism may result from p-CaMKII-bound SK2 channels and reveal new molecular targets to prevent lethal ventricular arrhythmias during acute hypoxia in cardiac hypertrophy. NEW & NOTEWORTHY We now show a new pathophysiological role of small-conductance Ca-activated K channels, which shorten the action potential duration and induce ventricular arrhythmias during hypoxia. We also demonstrate that small-conductance Ca-activated K channels interact with phosphorylated Ca/calmodulin-dependent protein kinase II at Thr in hypertrophied hearts.

PKA phosphorylation underlies functional recruitment of sarcolemmal SK2 channels in ventricular myocytes from hypertrophic hearts

“…implicate CaMKII-mediated phosphorylation of the channel in this process (Mizukami et al 2015;Tenma et al 2018). Indeed, our experiments with phospho-specific antibodies confirm that SK2 channels from TAB VMs are phosphorylated by serine/threonine kinases (Fig.…”

“…3A and B) supported enhanced activity of the kinase in TABs vs. Shams. Figure 3C and D shows enhanced phosphorylation of CaMKII at threonine-286, an indicator of CaMKII activation in hypertrophy (Tenma et al 2018). To test which of these two kinases is responsible for SK hyperphosphorylation in hypertrophy, we incubated myocytes from TABs with pharmacological inhibitors of CaMKII, KN93 (500 nmol L -1 ) and PKA, H89 (1 μmol L -1 ) for 30 min.…”

“…For example, contribution of SK channels to repolarization became obvious 10 min after the induction of acute myocardial infraction or 30 min of ischaemia in rat hearts (Gui et al 2012;Tenma et al 2018). Several hypotheses were proposed to explain this phenomenon including: (i) increased expression levels (Chang et al 2013a;Ni et al 2013); (ii) increased activity as a result of CaMKII phosphorylation (Mizukami et al 2015;Tenma et al 2018); and (iii) an increase in sensitivity to activating Ca 2+ as a result of dephosphorylation of SK-bound CaM given changes in the activities of SK-associated protein casein kinase 2 (CK2) and protein phosphatase 2A (PP2A) (Allen et al 2007;Bildl et al 2004;Yang et al 2015;. We previously reported that functional upregulation of plasmalemmal SK channels in VMs from hypertrophic rat hearts was not paralleled by increased expression levels (Kim et al 2017), suggesting that post-translational modifications may instead underlie enhanced channel activity.…”

Cardiac arrhythmias in patients with COVID‐19

“…Together, ventricular repolarization may be prolonged, leading to reentrant arrhythmias. By contrast, a shortening in repolarization time caused by small‐conductance Ca 2+ ‐activated K + (SK) channels may also be pro‐arrhythmic, especially where there is accompanying shortening in the effective refractory periods 55 . This would be expected to reduce cardiac excitation wavelength in turn predisposing to reentrant activity.…”

Modulation of SK Channels: Insight Into Therapeutics of Atrial Fibrillation

“…This contradictory phenomenon was mainly due to Ca 21 / calmodulin-dependent protein kinase II activation by autophosphorylation at Thr287, which increased the calcium sensitivity of SK channels and induced increased SK currents in AF patients. The activation of SK channels not only relies on the high intracellular Ca 21 but also on the Ca 21 sensitivity of SK channels [48,49].…”