Small-conductance Ca²⁺-activated K⁺ current is upregulated via the phosphorylation of CaMKII in cardiac hypertrophy from spontaneously hypertensive rats

Abstract

Left ventricular hypertrophy is associated with an increased risk of ventricular arrhythmias. However, the underlying molecular basis is poorly understood. It has been reported that small-conductance Ca(2+)-activated K(+) (SK) channels are involved in the pathogenesis of ventricular arrhythmias in heart failure. The present study aimed to test the hypothesis that SK channel activity is increased via the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)-dependent pathway in hypertensive cardiac hypertrophy. Normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs) were used. Whole cell membrane currents were recorded in isolated ventricular myocytes by the patch-clamp method, and apamin-sensitive K(+) current (IKAS), which is inhibited by apamin (100 nM), an SK channel blocker, was evaluated. IKAS at 40 mV was present in SHRs, whereas it was hardly detectable in WKY rats (0.579 ± 0.046 vs. 0.022 ± 0.062 pA/pF, both n = 6, P < 0.05). IKAS was almost completely abolished by 1 μM KN-93, a CaMKII inhibitor, in SHRs. Optical recordings of left ventricular anterior wall action potentials revealed that apamin prolonged the late phase of repolarization only in SHRs. Western blot analysis of SK channel protein isoforms demonstrated that SK2 was significantly increased in SHRs compared with WKY rats (SK2/GAPDH: 0.66 ± 0.07 vs. 0.40 ± 0.02, both n = 6, P < 0.05), whereas SK1 and SK3 did not differ between groups. In addition, autophosphorylated CaMKII was significantly increased in SHRs (phosphorylated CaMKII/GAPDH: 0.80 ± 0.06 vs. 0.58 ± 0.06, both n = 6, P < 0.05) despite a comparable total amount of CaMKII between groups. In conclusion, SK channels are upregulated via the enhanced activation of CaMKII in cardiac hypertrophy in SHRs.

Ca2+/Calmodulin-Dependent Protein Kinase II (CaMKII) Increases Small-Conductance Ca2+-Activated K+ Current in Patients with Chronic Atrial Fibrillation

“…CaMKII activity is enhanced in clinical and experimental models of AF [ 15 – 17 ]. SK channels are upregulated via the enhanced activation of CaMKII in hypertrophic hearts of spontaneously hypertensive rats [ 18 ]. Therefore, we hypothesized that increased CaMKII activity enhances the intracellular calcium sensitivity of SK channels in human chronic AF, and the present study was designed to test this hypothesis.…”

Arrhythmogenic β-adrenergic signaling in cardiac hypertrophy: The role of small-conductance calcium-activated potassium channels via activation of CaMKII

“…In contrast, in failing and hypertrophied hearts, these channels played an important role in the ventricular repolarization (Chua et al, 2011;Mizukami et al, 2015). We also reported that SK channels were upregulated via Kamada et al,Page 5 activation of CaMKII in hypertrophied rat hearts (Mitsuyama et al, 2014;Mizukami et al, 2015). At present, it is not well known that activation of SK channels produces antiarrhythmic or proarrhythmic functions (Chang et al, 2013;Chua et al, 2011).…”

“…It was reported that SK channels had a little contribution to the ventricular repolarization during action potentials of normal hearts (Nagy et al, 2009) . In contrast, in failing and hypertrophied hearts, these channels played an important role in the ventricular repolarization (Chua et al, 2011;Mizukami et al, 2015). We also reported that SK channels were upregulated via Kamada et al,Page 5 activation of CaMKII in hypertrophied rat hearts (Mitsuyama et al, 2014;Mizukami et al, 2015).…”

Systemic Sympathoexcitation Was Associated with Paraventricular Hypothalamic Phosphorylation of Synaptic CaMKIIα and MAPK/ErK

“…Although there was an increase in total MAPK/ErK in PVN total lysate (Figure 6b ; p < 0.05), confocal imaging revealed a decrease in MAPK/ErK—specifically—for eGFP positive PVN neurons in TLR4 Cre/− ISOP group (Figure 6a ; p < 0.01). Since it has been established that p-MAPK/ErK phosphorylates CaMKIIα (Mizukami et al, 2015 ; Yu et al, 2016 ), we further quantified the expression of PVN p-MAPK/ErK in the PVN. Although TLR4 Cre /− ISOP group recorded a higher PVN MAPK/ErK expression, there was a significant decrease in p-MAPK/ErK when compared with the TLR4 loxp / loxp ISOP group ( p < 0.001) after ISOP treatment.…”

“…Through its effect on TLR4 and NMDAR, βAR affects nNOS, and GABA neurotransmission in the brain; further increasing excitatory glutamatergic potentials (Sharma et al, 2011 ; Lethbridge et al, 2012 ; Di Mauro et al, 2013 ). Similarly, TLR4-mediated MAPK/ErK activation leads to inflammation via phosphorylation of calcium-calmodulin dependent kinase II alpha (CaMKIIα) (Mizukami et al, 2015 ; Yu et al, 2016 ). Thus, we hypothesize that attenuating MAPK/ErK inflammatory signaling events, in the PVN neurons, may reduce the severity of sympathoexcitation by reducing the phosphorylation of CaMKIIα.…”