Regulation of the transient outward K+ current by Ca2+/calmodulin-dependent protein kinases II in human atrial myocytes

Ca2+/calmodulin-dependent protein kinases II (CaMKII) have important functions in regulating cardiac excitability and contractility. In the present study, we examined whether CaMKII regulated the transient outward K+ current (I-to) in whole-cell patch-clamped human atrial myocytes. We found that a specific CaMKII inhibitor, KN-93 (20 mu mol/L), but not its inactive analog, KN-92, accelerated the inactivation of I-to (tau(fast): 66.9 +/- 4.4 versus 43.0 +/- 4.4 ms, n = 35; P < 0.0001) and inhibited its maintained component (at +60 mV, 4.9 +/- 0.4 versus 2.8 +/- 0.4 pA/pF, n = 35; P < 0.0001), leading to an increase in the extent of its inactivation. Similar effects were observed by dialyzing cells with a peptide corresponding to CaMKII residues 281 to 309 or with autocamtide-2-related inhibitory peptide and by external application of the calmodulin inhibitor calmidazolium, which also suppressed the effects of KN-93. Furthermore, the phosphatase inhibitor okadaic acid (500 nmol/L) slowed I-to inactivation, increased I-sus, and inhibited the effects of KN-93. Changes in [Ca2+](i) by dialyzing cells with approximate to 30 nmol/L Ca2+ or by using the fast Ca2+ buffer BAPTA had opposite effects on I-to. In BAPTA-loaded myocytes, I-to was less sensitive to KN-93. In myocytes from patients in chronic atrial fibrillation, characterized by a prominent I-sus, KN-93 still increased the extent of inactivation of I-to. Western blot analysis of atrial samples showed that delta-CaMKII expression was enhanced during chronic atrial fibrillation. In conclusion, CaMKII control the extent of inactivation of I-to in human atrial myocytes, a process that could contribute to I-to alterations observed during chronic atrial fibrillation.