Ca(2+)/Calmodulin-Dependent Protein Kinase II (CaMKII) Increases Small-Conductance Ca(2+)-Activated K(+) Current in Patients with Chronic Atrial Fibrillation

BACKGROUND: Increased small-conductance Ca(2+)-activated K(+) current (SK), abnormal intracellular Ca(2+) handling, and enhanced expression and activity of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) have been found in clinical and/or experimental models of atrial fibrillation (AF), but the cumulative effect of these phenomena and their mechanisms in AF are still unclear. This study aimed to test the hypothesis that CaMKII increases SK current in human chronic AF. MATERIAL/METHODS: Right atrial appendage tissues from patients with either sinus rhythm (SR) or AF and neonatal rat atrial myocytes were used. Patch clamp, qRT-PCR, and Western blotting techniques were used to perform the study. RESULTS: Compared to SR, the apamin-sensitive SK current (I(KAS)) was significantly increased, but the mRNA and protein levels of SK1, SK2, and SK3 were significantly decreased. In AF, the steady-state Ca(2+) response curve of I(KAS) was shifted leftward and the [Ca(2+)](i) level was significantly increased. CaMKII inhibitors (KN-93 or autocamtide-2-related inhibitory peptide (AIP)) reduced the I(KAS) in both AF and SR. The inhibitory effect of KN-93 or AIP on I(KAS) was greater in AF than in SR. The expression levels of calmodulin, CaMKII, and autophosphorylated CaMKII at Thr287 (but not at Thr286) were significantly increased in AF. Furthermore, KN-93 inhibited the expression of (Thr(287))p-CaMKII and SK2 in neonatal rat atrial myocytes. CONCLUSIONS: SK current is increased via the enhanced activation of CaMKII in patients with AF. This finding may explain the difference between SK current and channels expression in AF, and thus may provide a therapeutic target for AF.