© 1999 American Heart Association, Inc.
Cellular Biology |
Regulation of the Transient Outward K+ Current by Ca2+/Calmodulin-Dependent Protein Kinases II in Human Atrial Myocytes
From INSERM Unité 460 (S.T., J.-J.M., S.N.H.), Faculté de Médecine Xavier Bichat, Paris, France; Max-Delbrück Centre for Molecular Medicine (P.K., E.-G.K.), Berlin-Buch, Germany; and Service de Chirurgie Cardiaque (Y.P., C.A., M.L.-L.), Hôpital Xavier Bichat, Paris, France.
Correspondence to Pr Jean-Jacques Mercadier, INSERM Unité 460, Faculté de Médecine Xavier Bichat, 16, rue Henri Huchard, 75018 Paris, France. E-mail jjmercadier{at}wanadoo.fr
Abstract—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 (Ito) in
whole-cell patch-clamped human atrial myocytes. We found that a
specific CaMKII inhibitor, KN-93 (20 µmol/L), but
not its inactive analog, KN-92, accelerated the inactivation of
Ito (
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 Ito inactivation,
increased Isus, and inhibited the effects of
KN-93. Changes in [Ca2+]i by dialyzing cells
with 
30 nmol/L Ca2+ or by using the fast
Ca2+ buffer BAPTA had opposite effects on
Ito. In BAPTA-loaded myocytes,
Ito was less sensitive to KN-93. In myocytes
from patients in chronic atrial fibrillation, characterized by a
prominent Isus, KN-93 still increased the
extent of inactivation of Ito. Western blot
analysis of atrial samples showed that 
-CaMKII expression
was enhanced during chronic atrial fibrillation. In conclusion, CaMKII
control the extent of inactivation of Ito in
human atrial myocytes, a process that could contribute to
Ito alterations observed during chronic
atrial fibrillation.
Key Words: KN-93 • K+ channel • -CaMKII • atrial fibrillation • heart
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