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

Kazuya Mizukami, Hisashi Yokoshiki, Hirofumi Mitsuyama, Masaya Watanabe, Taro Tenma, Shingo Takada, Hiroyuki Tsutsui

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14 Citations (Scopus)


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 Ca2+-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 Ca2+/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.

Original languageEnglish
Pages (from-to)H1066-H1074
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number6
Publication statusPublished - Sep 18 2015
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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