Affiliation:
1. 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.
Abstract
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 μmol/L), but not its inactive analog, KN-92, accelerated the inactivation of
I
to
(τ
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 ≈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 δ-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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine,Physiology
Cited by
154 articles.
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