Calmodulin kinase II inhibition shortens action potential duration by upregulation of K+ currents

Jingdong Li, Céline Marionneau, Rong Zhang, Vaibhavi Shah, Johannes W Hell, Jeanne M. Nerbonne, Mark E. Anderson

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

The multifunctional Ca/calmodulin-dependent protein kinase II (CaMKII) is activated by elevated intracellular Ca (Cai), and mice with chronic myocardial CaMKII inhibition (Inh) resulting from transgenic expression of a CaMKII inhibitory peptide (AC3-I) unexpectedly showed action potential duration (APD) shortening. Inh mice exhibit increased L-type Ca current (ICa), because of upregulation of protein kinase A (PKA) activity, and decreased CaMKII-dependent phosphorylation of phospholamban (PLN). We hypothesized that CaMKII is a molecular signal linking Cai to repolarization. Whole cell voltage-clamp recordings revealed that the fast transient outward current (Ito,f) and the inward rectifier current (IK1) were selectively upregulated in Inh, compared with wild-type (WT) and transgenic control, mice. Breeding Inh mice with mice lacking PLN returned Ito,f and IK1 to control levels and equalized the APD and QT intervals in Inh mice to control and WT levels. Dialysis of AC3-I into WT cells did not result in increased Ito,f or IK1, suggesting that enhanced cardiac repolarization in Inh mice is an adaptive response to chronic CaMKII inhibition rather than an acute effect of reduced CaMKII activity. Increasing PKA activity, by cell dialysis with cAMP, or inhibition of PKA did not affect IK1 in WT cells. Dialysis of WT cells with cAMP also reduced Ito,f, suggesting that PKA upregulation does not increase repolarizing K currents in Inh mice. These findings provide novel in vivo and cellular evidence that CaMKII links Cai to cardiac repolarization and suggest that PLN may be a critical CaMKII target for feedback regulation of APD in ventricular myocytes.

Original languageEnglish (US)
Pages (from-to)1092-1099
Number of pages8
JournalCirculation Research
Volume99
Issue number10
DOIs
StatePublished - Nov 2006
Externally publishedYes

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Keywords

  • Ca/calmodulin-dependent protein kinase II
  • Calcium signaling
  • Repolarization

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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