Adrenergic regulation of a key cardiac potassium channel can contribute to atrial fibrillation: evidence from an I Ks transgenic mouse

Inherited gain-of-function mutations of genes coding for subunits of the heart slow potassium (I Ks) channel can cause familial atrial fibrillation (AF). Here we consider a potentially more prevalent mechanism and hypothesize that beta-adrenergic receptor (beta-AR)-mediated regulation of the I Ks ch...

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Bibliographic Details
Published in:The Journal of physiology 2008-01, Vol.586 (2), p.627-637
Main Authors: Sampson, Kevin J, Terrenoire, Cecile, Cervantes, Daniel O, Kaba, Riyaz A, Peters, Nicholas S, Kass, Robert S
Format: Article
Language:English
Subjects:
Adrenergic beta-Agonists - pharmacology
Animals
Atrial Fibrillation - etiology
Atrial Fibrillation - metabolism
Atrial Fibrillation - pathology
Computer Simulation
Electrocardiography
Electrophysiology
Female
Isoproterenol - pharmacology
Male
Mice
Mice, Transgenic
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - pathology
Patch-Clamp Techniques
Potassium Channels, Voltage-Gated - drug effects
Potassium Channels, Voltage-Gated - genetics
Potassium Channels, Voltage-Gated - metabolism
Receptors, Adrenergic, beta - metabolism
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Summary:Inherited gain-of-function mutations of genes coding for subunits of the heart slow potassium (I Ks) channel can cause familial atrial fibrillation (AF). Here we consider a potentially more prevalent mechanism and hypothesize that beta-adrenergic receptor (beta-AR)-mediated regulation of the I Ks channel, a natural gain-of-function pathway, can also lead to AF. Using a transgenic I Ks channel mouse model, we studied the role of the channel and its regulation by beta-AR stimulation on atrial arrhythmias. In vivo administration of isoprenaline (isoproterenol) predisposes I Ks channel transgenic mice but not wild-type (WT) littermates that lack I Ks to prolonged atrial arrhythmias. Patch-clamp analysis demonstrated expression and isoprenaline-mediated regulation of I Ks in atrial myocytes from transgenic but not WT littermates. Furthermore, computational modelling revealed that beta-AR stimulation-dependent accumulation of open I Ks channels accounts for the pro-arrhythmic substrate. Our results provide evidence that beta-AR-regulated I Ks channels can play a role in AF and imply that specific I Ks deregulation, perhaps through disruption of the I Ks macromolecular complex necessary for beta-AR-mediated I Ks channel regulation, may be a novel therapeutic strategy for treating this most common arrhythmia.
ISSN:0022-3751
1469-7793
DOI:10.1113/jphysiol.2007.141333