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 CaMKIIδ_C, both acutely in rabbit ventricular myocytes (24-hour adenoviral gene transfer) and chronically in CaMKIIδ_C-transgenic mice, on transient outward potassium current (I_to), and inward rectifying current (I_K1). Acute and chronic CaMKII overexpression increases I_to,slow amplitude and expression of the underlying channel protein K_V1.4. Chronic but not acute CaMKII overexpression causes downregulation of I_to,fast, as well as K_V4.2 and KChIP2, suggesting that K_V1.4 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 I_to components, but these effects were acutely reversed by AIP (CaMKII inhibitor), suggesting that CaMKII activity directly accelerates I_to recovery. Expression levels of I_K1 and Kir2.1 mRNA were downregulated by CaMKII overexpression. CaMKII acutely increased I_K1, based on inhibition by AIP (in both models). CaMKII overexpression in mouse prolonged APD (consistent with reduced I_to,fast and I_K1), whereas CaMKII overexpression in rabbit shortened APD (consistent with enhanced I_K1 and I_to,slow and faster I_to 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 I_to and I_K1 with complex consequences on APD.