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 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.
Sampson
Kevin J
KJ
Department of Pharmacology, Columbia University Medical Center, 630 W 168th St, New York, NY 10032, USA.
Terrenoire
Cecile
C
Cervantes
Daniel O
DO
Kaba
Riyaz A
RA
Peters
Nicholas S
NS
Kass
Robert S
RS
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D003198:Computer Simulation; D004562:Electrocardiography; D004594:Electrophysiology; D005260:Female; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
D000318:Adrenergic beta-Agonists; D024642:Potassium Channels, Voltage-Gated; D011943:Receptors, Adrenergic, beta; C059983:potassium channel protein I(sk); D007545:Isoproterenol