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

Abstract

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.

• Authors: Kevin J Sampson, Cecile Terrenoire, Daniel O Cervantes, Riyaz A Kaba, Nicholas S Peters, Robert S Kass
• Journal: The Journal of physiology (J Physiol) Vol. 586 Issue 2 Pg. 627-37 (Jan 15 2008) ISSN: 0022-3751 [Print] England
• PMID: 18006587 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adrenergic beta-Agonists
• Potassium Channels, Voltage-Gated
• Receptors, Adrenergic, beta
• potassium channel protein I(sk)
• Isoproterenol

Topics

• Adrenergic beta-Agonists (pharmacology)
• Animals
• Atrial Fibrillation (etiology, metabolism, pathology)
• Computer Simulation
• Electrocardiography
• Electrophysiology
• Female
• Isoproterenol (pharmacology)
• Male
• Mice
• Mice, Transgenic
• Myocytes, Cardiac (metabolism, pathology)
• Patch-Clamp Techniques
• Potassium Channels, Voltage-Gated (drug effects, genetics, metabolism)
• Receptors, Adrenergic, beta (metabolism)