Understanding molecular mechanisms involved in atrial tissue remodeling and arrhythmogenesis in atrial fibrillation (AF) is essential for developing specific therapeutic approaches. Two-pore-domain ...potassium (K
2P
) channels modulate cellular excitability, and TASK-1 (K
2P
3.1) currents were recently shown to alter atrial action potential duration in AF and heart failure (HF). Finding animal models of AF that closely resemble pathophysiological alterations in human is a challenging task. This study aimed to analyze murine cardiac expression patterns of K
2P
channels and to assess modulation of K
2P
channel expression in murine models of AF and HF. Expression of cardiac K
2P
channels was quantified by real-time qPCR and immunoblot in mouse models of AF cAMP-response element modulator (CREM)-IbΔC-X transgenic animals or HF (cardiac dysfunction induced by transverse aortic constriction, TAC). Cloned murine, human, and porcine TASK-1 channels were heterologously expressed in
Xenopus laevis
oocytes. Two-electrode voltage clamp experiments were used for functional characterization. In murine models, among members of the K
2P
channel family, TASK-1 expression displayed highest levels in both atrial and ventricular tissue samples. Furthermore, K
2P
2.1, K
2P
5.1, and K
2P
6.1 showed significant expression levels. In CREM-transgenic mice, atrial expression of TASK-1 was significantly reduced in comparison with wild-type animals. In a murine model of TAC-induced pressure overload, ventricular TASK-1 expression remained unchanged, while atrial TASK-1 levels were significantly downregulated. When heterologously expressed in
Xenopus oocytes
, currents of murine, porcine, and human TASK-1 displayed similar characteristics. TASK-1 channels display robust cardiac expression in mice. Murine, porcine, and human TASK-1 channels share functional similarities. Dysregulation of atrial TASK-1 expression in murine AF and HF models suggests a mechanistic contribution to arrhythmogenesis.
The fight-or-flight response (FFR), a physiological acute stress reaction, involves positive chronotropic and inotropic effects on heart muscle cells mediated through β-adrenoceptor activation. ...Increased systolic calcium is required to enable stronger heart contractions whereas elevated potassium currents are to limit the duration of the action potentials and prevent arrhythmia. The latter effect is accomplished by an increased functional activity of the K
v
7.1 channel encoded by
KCNQ1
. Current knowledge, however, does not sufficiently explain the full extent of rapid K
v
7.1 activation and may hence be incomplete. Using inducible genetic
KCNQ1
complementation in
KCNQ1
-deficient human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we here reinvestigate the functional role of K
v
7.1 in adapting human CMs to adrenergic stress. Under baseline conditions, K
v
7.1 was barely detectable at the plasma membrane of hiPSC-CMs, yet it fully protected these from adrenergic stress-induced beat-to-beat variability of repolarization and
torsade des pointes
-like arrhythmia. Furthermore, isoprenaline treatment increased field potential durations specifically in KCNQ1-deficient CMs to cause these adverse macroscopic effects. Mechanistically, we find that the protective action by K
v
7.1 resides in a rapid translocation of channel proteins from intracellular stores to the plasma membrane, induced by adrenergic signaling. Gene silencing experiments targeting RAB GTPases, mediators of intracellular vesicle trafficking, showed that fast K
v
7.1 recycling under acute stress conditions is RAB4A-dependent.Our data reveal a key mechanism underlying the rapid adaptation of human cardiomyocytes to adrenergic stress. These findings moreover aid to the understanding of disease pathology in long QT syndrome and bear important implications for safety pharmacological screening.
The fight-or-flight response (FFR), a physiological acute stress reaction, involves positive chronotropic and inotropic effects on heart muscle cells mediated through β-adrenoceptor activation. ...Increased systolic calcium is required to enable stronger heart contractions whereas elevated potassium currents are to limit the duration of the action potentials and prevent arrhythmia. The latter effect is accomplished by an increased functional activity of the K
7.1 channel encoded by
. Current knowledge, however, does not sufficiently explain the full extent of rapid K
7.1 activation and may hence be incomplete. Using inducible genetic
complementation in
-deficient human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we here reinvestigate the functional role of K
7.1 in adapting human CMs to adrenergic stress. Under baseline conditions, K
7.1 was barely detectable at the plasma membrane of hiPSC-CMs, yet it fully protected these from adrenergic stress-induced beat-to-beat variability of repolarization and
-like arrhythmia. Furthermore, isoprenaline treatment increased field potential durations specifically in KCNQ1-deficient CMs to cause these adverse macroscopic effects. Mechanistically, we find that the protective action by K
7.1 resides in a rapid translocation of channel proteins from intracellular stores to the plasma membrane, induced by adrenergic signaling. Gene silencing experiments targeting RAB GTPases, mediators of intracellular vesicle trafficking, showed that fast K
7.1 recycling under acute stress conditions is RAB4A-dependent.Our data reveal a key mechanism underlying the rapid adaptation of human cardiomyocytes to adrenergic stress. These findings moreover aid to the understanding of disease pathology in long QT syndrome and bear important implications for safety pharmacological screening.
Abstract only
Transgenic mice with heart directed expression of transcription factor CREM‐IbΔC‐X (TG) develop atrial alterations including dilatation, impaired electrical conduction and impaired ...regulation of intracellular Ca
2+
preceding spontaneous‐onset atrial fibrillation. Here, we studied whether CREM‐IbΔC‐X is linked to proarrhythmic alterations in ventricular cardiomyocytes (CMs). Action potentials were prolonged in TG CMs along with reduced mRNA of the I
to
underlying channel subunit Kv4.2 as compared to wild‐type (WT) CMs. In TG vs. WT CMs Ca
2+
transient amplitude was unaltered under basal conditions but increased under stimulation with isoproterenol. Under both conditions Ca
2+
release was retarded but the Ca
2+
decay was accelerated in TG vs. WT CMs. The frequency of Ca
2+
sparks was enhanced while spark amplitude was reduced in TG vs. WT CMs. Stress stimulation protocols revealed an enhanced rate of spontaneous Ca
2+
releases in TG vs. WT CMs. Hence, human cardiac isoform CREM‐IbΔC‐X is linked to an increased susceptibility to arrhythmia possibly by regulating the transcription of genes modulating AP shape and duration and intracellular Ca
2+
cycling. Supported by IZKF Münster
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