Ca/calmodulin kinase II differentially modulates potassium currents

Stefan Wagner, Elena Hacker, Eleonora Grandi, Sarah L. Weber, Nataliya Dybkova, Samuel Sossalla, Thomas Sowa, Larissa Fabritz, Paulus Kirchhof, Donald M Bers, Lars S. Maier

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

Background-Potassium currents contribute to action potential duration (APD) and arrhythmogenesis. In heart failure, Ca/calmodulin-dependent protein kinase II (CaMKII) is upregulated and can alter ion channel regulation and expression. Methods and Results-We examine the influence of overexpressing cytoplasmic CaMKIIδC, both acutely in rabbit ventricular myocytes (24-hour adenoviral gene transfer) and chronically in CaMKIIδC-transgenic mice, on transient outward potassium current (Ito), and inward rectifying current (IK1). Acute and chronic CaMKII overexpression increases Ito, slow amplitude and expression of the underlying channel protein KV1.4. Chronic but not acute CaMKII overexpression causes downregulation of Ito, fast, as well as KV4.2 and KChIP2, suggesting that KV1.4 expression responds faster and oppositely to K V4.2 on CaMKII activation. These amplitude changes were not reversed by CaMKII inhibition, consistent with CaMKII-dependent regulation of channel expression and/or trafficking. CaMKII (acute and chronic) greatly accelerated recovery from inactivation for both Ito components, but these effects were acutely reversed by AIP (CaMKII inhibitor), suggesting that CaMKII activity directly accelerates Ito recovery. Expression levels of IK1 and Kir2.1 mRNA were downregulated by CaMKII overexpression. CaMKII acutely increased IK1, based on inhibition by AIP (in both models). CaMKII overexpression in mouse prolonged APD (consistent with reduced Ito, fast and IK1), whereas CaMKII overexpression in rabbit shortened APD (consistent with enhanced IK1 and I to, slow and faster Ito recovery). Computational models allowed discrimination of contributions of different channel effects on APD. Conclusion-CaMKII has both acute regulatory effects and chronic expression level effects on Ito and IK1 with complex consequences on APD.

Original languageEnglish (US)
Pages (from-to)285-294
Number of pages10
JournalCirculation: Arrhythmia and Electrophysiology
Volume2
Issue number3
DOIs
StatePublished - Jun 2009

Keywords

  • Action potentials
  • Arrhythmia
  • Electrophysiology
  • Heart failure
  • Potassium

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Wagner, S., Hacker, E., Grandi, E., Weber, S. L., Dybkova, N., Sossalla, S., Sowa, T., Fabritz, L., Kirchhof, P., Bers, D. M., & Maier, L. S. (2009). Ca/calmodulin kinase II differentially modulates potassium currents. Circulation: Arrhythmia and Electrophysiology, 2(3), 285-294. https://doi.org/10.1161/CIRCEP.108.842799