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Adrenergic regulation of a key cardiac potassium channel can contribute to atrial fibrillation: evidence from an I Ks transgenic mouse
Author(s) -
Sampson Kevin J.,
Terrenoire Cecile,
Cervantes Daniel O.,
Kaba Riyaz A.,
Peters Nicholas S.,
Kass Robert S.
Publication year - 2008
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2007.141333
Subject(s) - atrial fibrillation , potassium channel , adrenergic , genetically modified mouse , medicine , transgene , cardiology , key (lock) , potassium , endocrinology , microbiology and biotechnology , biology , chemistry , receptor , gene , genetics , ecology , organic chemistry
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 β‐adrenergic receptor (β‐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 β‐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 β‐AR stimulation‐dependent accumulation of open I Ks channels accounts for the pro‐arrhythmic substrate. Our results provide evidence that β‐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 β‐AR‐mediated I Ks channel regulation, may be a novel therapeutic strategy for treating this most common arrhythmia.