Ca2+/Calmodulin-Dependent Protein Kinase II (CaMKII) Increases Small-Conductance Ca2+-Activated K+ Current in Patients with Chronic Atrial Fibrillation

Abstract

BackgroundIncreased small-conductance Ca2+-activated K+ current (SK), abnormal intracellular Ca2+ handling, and enhanced expression and activity of Ca2+/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/MethodsRight 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.ResultsCompared to SR, the apamin-sensitive SK current (IKAS) was significantly increased, but the mRNA and protein levels of SK1, SK2, and SK3 were significantly decreased. In AF, the steady-state Ca2+ response curve of IKAS was shifted leftward and the [Ca2+]i level was significantly increased. CaMKII inhibitors (KN-93 or autocamtide-2-related inhibitory peptide (AIP)) reduced the IKAS in both AF and SR. The inhibitory effect of KN-93 or AIP on IKAS 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 (Thr287)p-CaMKII and SK2 in neonatal rat atrial myocytes.ConclusionsSK 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.

Small and Intermediate Calcium Activated Potassium Channels in the Heart: Role and Strategies in the Treatment of Cardiovascular Diseases

“…Li et al (2011) showed that SK2 current density is bigger in atrial cells from patients diagnosed with persistent AF (at least 6 months) than in non-AF patients. At a molecular level, CAMKII levels are increased in human AF atrial cells, associated with a left shift of the SK calcium dose-response curve and bigger currents (Fan et al, 2018). Oppositely, in atrial biopsies from chronic AF patients (more than 6 months preceding a medical surgery), the SK1, SK2, (Yu et al, 2012) or SK3 (Skibsbye et al, 2014) transcripts and protein levels are reduced compared with atrial biopsies obtained from patients with sinus rhythm.…”

Atrial fibrillation and its arrhythmogenesis associated with insulin resistance

“…CaMKII hyperactivity has been demonstrated to be causatively associated with AF and ventricular arrhythmias in heart failure through modulating calcium handling–related protein activities [31, 32]. Recently, research revealed that CaMKII increases small-conductance Ca 2+ -activated K + current in atria from patients with AF [33]. A recent study showed ox-CaMKII–mediated ventricular arrhythmia in a mouse model of Duchenne muscular dystrophy [34].…”

Molecular Basis of Atrial Fibrillation Initiation and Maintenance

“…Thus, contrary to what happens with contraction, the PDE3 or PDE4 control on propensity of 5-HT-evoked arrhythmias on human atrial trabeculae from patients in sinus rhythm or with paroxysmal AF, is lost in persistent AF [93]. 5-HT stimulation has been shown to increase I f [94] and I Ca,L [91,94] in HAMs, but less than β-adrenergic stimulation [91,95] and without regulation of PDE3 or PDE4 [90].…”

“…CaMKII has also been shown to autophosphorylate independently of Epac2 in atrial appendage samples of AF patients. Thus, CaMKII autophosphorylation increased Ca 2+ sensitivity of apamin sensitive small-conductance Ca 2+ -activated K + current (I KAS ) in AF [90].…”