Ca/Calmodulin Kinase II Differentially Modulates Potassium Currents

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 CaMKII delta(C), both acutely in rabbit ventricular myocytes (24-hour adenoviral gene transfer) and chronically in CaMKII delta(C)-transgenic mice, on transient outward potassium current (I-to), and inward rectifying current (I-K1). Acute and chronic CaMKII overexpression increases I-to,I-slow amplitude and expression of the underlying channel protein K(v)1.4. Chronic but not acute CaMKII overexpression causes downregulation of I-to,I-fast, as well as K(v)4.2 and KChIP2, suggesting that K(v)1.4 expression responds faster and oppositely to K(v)4.2 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,I-fast and I-K1, whereas CaMKII overexpression in rabbit shortened APD (consistent with enhanced I-K1 and I-to,I-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. (Circ Arrhythmia Electrophysiol. 2009;2:285-294.)