Regulation of the Transient Outward K ⁺ Current by Ca ²⁺ /Calmodulin-Dependent Protein Kinases II in Human Atrial Myocytes

Abstract

Ca(2+)/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 micromol/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 [Ca(2+)](i) by dialyzing cells with approximately 30 nmol/L Ca(2+) or by using the fast Ca(2+) 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.

Calcium–Calmodulin-Dependent Kinase II Modulates Kv4.2 Channel Expression and Upregulates Neuronal A-Type Potassium Currents

“…For example, in murine colonic myocytes, inhibition of CaMKII with KN-93 or KN-62 causes an increased rate of A-type channel inactivation and slows the recovery from inactivation with no change in peak current amplitude (Koh et al, 1999). In human atrial myocytes, KN-93 also accelerates the inactivation of the transient outward potassium current (I to ), and in this case the amplitude of the maintained component is also decreased (Tessier et al, 1999). Thus, CaMKII seems to have similar effects on Kv1.4, which also mediates an A-type current.…”

Atrial Ionic Remodeling Induced by Atrial Tachycardia in the Presence of Congestive Heart Failure

“…Although there is evidence for transcriptional downregulation as a mechanism for ATinduced decreases in ion-current density in animal models 21 and in humans, 3,22 Schotten et al 23 did not find I Ca ␣ 1c -protein to be reduced in atrial samples from AF patients. Therefore, other mechanisms at the regulatory level, such as enhanced phosphatase activity (Christ et al, unpublished observations) and alterations in Ca 2ϩ -calmodulin kinase II, 24 may also be involved. Further work on mechanisms underlying AT-and CHF-induced ion-channel dysfunction would be of great interest.…”

Ca2+ Controls Functional Expression of the Cardiac K+ Transient Outward Current via the Calcineurin Pathway

“…Unidentified common pathway(s) may underlie a down-regulation of the expression of I to channels in all these pathological conditions. A possible candidate for triggering such channel remodeling could be the altered level of intracel- (4). At the molecular level, shal-type voltage-gated K ϩ channels (in rat predominantly Kv4.2 (5)) are the pore-forming subunits of the I to channel that are regulated by auxiliary subunits (5,6).…”