Ca/calmodulin kinase II differentially modulates potassium currents
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Colleges, School and Institutes
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 CaMKIIdelta(C), both acutely in rabbit ventricular myocytes (24-hour adenoviral gene transfer) and chronically in CaMKIIdelta(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. CONCLUSIONS CaMKII has both acute regulatory effects and chronic expression level effects on I(to) and I(K1) with complex consequences on APD.
|Number of pages||10|
|Journal||Circulation Arrhythmia and Electrophysiology|
|Publication status||Published - 1 Jan 2009|