Ca/Calmodulin Kinase II Differentially Modulates Potassium Currents

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 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 _V 1.4. Chronic but not acute CaMKII overexpression causes downregulation of I _to,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,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.