Background: A recent genome-wide association study identified a susceptibility locus for atrial fibrillation at the KCNN3 gene. Since the KCNN3 gene encodes for a small conductance calcium-activated potassium channel, we hypothesized that overexpression of the SK3 channel increases susceptibility to cardiac arrhythmias.
Methods And Results: We characterized the cardiac electrophysiological phenotype of a mouse line with overexpression of the SK3 channel. We generated homozygote (SK3(T/T)) and heterozygote (SK3(+/T)) mice with overexpression of the channel and compared them with wild-type (WT) controls. We observed a high incidence of sudden death among SK3(T/T) mice (7 of 19 SK3(T/T) mice). Ambulatory monitoring demonstrated that sudden death was due to heart block and bradyarrhythmias. SK3(T/T) mice displayed normal body weight, temperature, and cardiac function on echocardiography; however, histological analysis demonstrated that these mice have abnormal atrioventricular node morphology. Optical mapping demonstrated that SK3(T/T) mice have slower ventricular conduction compared with WT controls (SK3(T/T) vs. WT; 0.45 ± 0.04 vs. 0.60 ± 0.09 mm/ms, P = 0.001). Programmed stimulation in 1-month-old SK3(T/T) mice demonstrated inducible atrial arrhythmias (50% of SK3(T/T) vs. 0% of WT mice) and also a shorter atrioventricular nodal refractory period (SK3(T/T) vs. WT; 43 ± 6 vs. 52 ± 9 ms, P = 0.02). Three-month-old SK3(T/T) mice on the other hand displayed a trend towards a more prolonged atrioventricular nodal refractory period (SK3(T/T) vs. WT; 61 ± 1 vs. 52 ± 6 ms, P = 0.06).
Conclusion: Overexpression of the SK3 channel causes an increased risk of sudden death associated with bradyarrhythmias and heart block, possibly due to atrioventricular nodal dysfunction.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896252 | PMC |
| http://dx.doi.org/10.1093/cvr/cvt269 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Urinary bladder instability induced by selective suppression of the murine small conductance calcium-activated potassium (SK3) channel.
J Physiol
September 2003
Department of Pharmacology, University of Vermont, Burlington 05405-0068, USA.
Small conductance, calcium-activated potassium (SK) channels have an important role in determining the excitability and contractility of urinary bladder smooth muscle. Here, the role of the SK isoform SK3 was examined by altering expression levels of the SK3 gene using a mouse model that conditionally overexpresses SK3 channels (SK3T/T). Prominent SK3 immunostaining was found in both the smooth muscle (detrusor) and urothelium layers of the urinary bladder.
View Article and Find Full Text PDFAltered expression of small-conductance Ca2+-activated K+ (SK3) channels modulates arterial tone and blood pressure.
Circ Res
July 2003
Department of Pharmacology, University of Vermont, 89 Beaumont Ave, Burlington, VT 05405, USA.
The endothelium is a critical regulator of vascular tone, and dysfunction of the endothelium contributes to numerous cardiovascular pathologies. Recent studies suggest that apamin-sensitive, small-conductance, Ca2+-activated K+ channels may play an important role in active endothelium-dependent vasodilations, and expression of these channels may be altered in disease states characterized by vascular dysfunction. Here, we used a transgenic mouse (SK3T/T) in which SK3 expression levels can be manipulated with dietary doxycycline (DOX) to test the hypothesis that the level of expression of the SK subunit, SK3, in endothelial cells alters arterial function and blood pressure.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!