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(Circulation Research. 2008;103:733.)
© 2008 American Heart Association, Inc.

Cellular Biology

Mechanisms Underlying Rate-Dependent Remodeling of Transient Outward Potassium Current in Canine Ventricular Myocytes

Ling Xiao, Pierre Coutu, Louis R. Villeneuve, Artavazd Tadevosyan, Ange Maguy, Sabrina Le Bouter, Bruce G. Allen, Stanley Nattel

From the Department of Medicine (L.X., P.C., L.R.V., A.T., A.M., S.L.B., B.G.A., S.N.), Montreal Heart Institute and Université de Montréal; and Department of Pharmacology and Therapeutics (L.X., B.G.A., S.N.), McGill University, Montreal, Quebec, Canada.

Correspondence to Stanley Nattel, 5000 Belanger St East, Montréal, Québec, H1T 1C8, Canada. E-mail stanley.nattel{at}icm-mhi.org

Transient outward K⁺ current (I_to) downregulation following sustained tachycardia in vivo is usually attributed to tachycardiomyopathy. This study assessed potential direct rate regulation of cardiac I_to and underlying mechanisms. Cultured adult canine left ventricular cardiomyocytes (37°C) were paced continuously at 1 or 3 Hz for 24 hours. I_to was recorded with whole-cell patch clamp. The 3-Hz pacing reduced I_to by 44% (P<0.01). Kv4.3 mRNA and protein expression were significantly reduced (by 30% and 40%, respectively) in 3-Hz paced cells relative to 1-Hz cells, but KChIP2 expression was unchanged. Prevention of Ca²⁺ loading with nimodipine or calmodulin inhibition with W-7, A-7, or W-13 eliminated 3-Hz pacing-induced I_to downregulation, whereas downregulation was preserved in the presence of valsartan. Inhibition of Ca²⁺/calmodulin-dependent protein kinase (CaMK)II with KN93, or calcineurin with cyclosporin A, also prevented I_to downregulation. CaMKII-mediated phospholamban phosphorylation at threonine 17 was increased in 3-Hz paced cells, compatible with enhanced CaMKII activity, with functional significance suggested by acceleration of the Ca²⁺_i transient decay time constant (Indo 1-acetoxymethyl ester microfluorescence). Total phospholamban expression was unchanged, as was expression of Na⁺/Ca²⁺ exchange and sarcoplasmic reticulum Ca²⁺-ATPase proteins. Nuclear localization of the calcineurin-regulated nuclear factor of activated T cells (NFAT)c3 was increased in 3-Hz paced cells compared to 1-Hz (immunohistochemistry, immunoblot). INCA-6 inhibition of NFAT prevented I_to reduction in 3-Hz paced cells. Calcineurin activity increased after 6 hours of 3-Hz pacing. CaMKII inhibition prevented calcineurin activation and NFATc3 nuclear translocation with 3-Hz pacing. We conclude that tachycardia downregulates I_to expression, with the Ca²⁺/calmodulin-dependent CaMKII and calcineurin/NFAT systems playing key Ca²⁺-sensing and signal-transducing roles in rate-dependent I_to control.

Key Words: potassium channels • calcium • calmodulin • remodeling • arrhythmias

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