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J Physiol Volume 586, Number 2, 627-637, January 15, 2008 DOI: 10.1113/jphysiol.2007.141333
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CARDIOVASCULAR

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

 Kevin J. Sampson1, Cecile Terrenoire1, Daniel O. Cervantes1, Riyaz A. Kaba2, Nicholas S. Peters2 and Robert S. Kass1

1 Department of Pharmacology, Columbia University Medical Center, New York, NY, USA
2 Department of Cardiac Electrophysiology, Imperial College, St Mary's Hospital, London, UK

Inherited gain-of-function mutations of genes coding for subunits of the heart slow potassium (IKs) channel can cause familial atrial fibrillation (AF). Here we consider a potentially more prevalent mechanism and hypothesize that β-adrenergic receptor (β-AR)-mediated regulation of the IKs channel, a natural gain-of-function pathway, can also lead to AF. Using a transgenic IKs channel mouse model, we studied the role of the channel and its regulation by β-AR stimulation on atrial arrhythmias. In vivo administration of isoprenaline (isoproterenol) predisposes IKs channel transgenic mice but not wild-type (WT) littermates that lack IKs to prolonged atrial arrhythmias. Patch-clamp analysis demonstrated expression and isoprenaline-mediated regulation of IKs in atrial myocytes from transgenic but not WT littermates. Furthermore, computational modelling revealed that β-AR stimulation-dependent accumulation of open IKs channels accounts for the pro-arrhythmic substrate. Our results provide evidence that β-AR-regulated IKs channels can play a role in AF and imply that specific IKs deregulation, perhaps through disruption of the IKs macromolecular complex necessary for β-AR-mediated IKs channel regulation, may be a novel therapeutic strategy for treating this most common arrhythmia.

(Received 24 July 2007; accepted after revision 12 November 2007; first published online 15 November 2007)
Corresponding author R. S. Kass: Department of Pharmacology, Columbia University Medical Center, 630 W 168th St, New York, NY 10032, USA. Email: rsk20{at}columbia.edu

K. J. Sampson and C. Terrenoire contributed equally to this work. This paper has online supplemental material.




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