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Dissection of the voltage-activated potassium outward currents in adult mouse ventricular myocytes: I to,f, I to,s, I K,slow1, I K,slow2, and I ss

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Abstract

Voltage-activated outward K+ currents (I Kv) are essential for cardiac repolarization and are major factors in the electrophysiological remodeling and arrhythmias seen in heart disease. Mouse models have been useful for understanding cardiac electrophysiology. However, previous methods for separating and quantifying the components of I Kv in mouse myocardium have yielded inconsistencies. In this study, we developed a statistically rigorous method to uniquely quantify various I Kv in adult mouse ventricular myocytes, and concluded that tri-exponential functions combined with depolarizing pulses of duration greater than 20 s are essential to adequately separate the different I Kv components. This method enabled us to reliably dissect the kinetic components of the decay phase of I Kv into fast (I to), intermediate (KV1.5-encoded I K,slow1) and slow (KV2-encoded I K,slow2) components. The most rapid kinetic phase, I to, can be further dissected into fast (KV4-encoded I to,f) and slow (KV1.4-encoded I to,s) components by measuring recovery from inactivation, voltage-dependence of activation and sensitivity to HpTx-2 and 4-AP. The applicability of our dissection method was validated using transgenic mice over-expressing dominant-negative KV1.1 transgene which largely abolished the 4-AP-sensitive portion of I to (i.e., I to,s) and the I K,slow1 component. We also applied our method to Irx5-deficient mice and verified selective elevations of I to in endocardial myocytes. Our method should prove useful in future electrophysiological studies using mouse.

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Acknowledgments

The authors thank Roman Pekhletski, Farzad Izaddoustdar, and Islam M. Zahadul for technical discussion and support. K.-H.K. was supported in part by graduate studentships from the Ontario Graduate Scholarship in Science and Technology program. M.J.M was supported by a grant from John R. Oishei Foundation. This study was funded by grants from Heart & Stroke Foundation of Ontario (T6485) to P.H.B. P.H.B. holds a Career Investigator Award from the Heart & Stroke Foundation of Ontario.

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Authors and Affiliations

  1. Departments of Physiology and Medicine, University of Toronto, 150 College St., Toronto, ON, M5S 3E2, Canada

    Jie Liu, Kyoung-Han Kim & Peter H. Backx

  2. Division of Cardiology, University Health Network, Toronto, ON, Canada

    Jie Liu, Kyoung-Han Kim & Peter H. Backx

  3. The Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA, USA

    Barry London

  4. Department of Physiology and Biophysics, University at Buffalo, The State University of New York, Buffalo, NY, USA

    Michael J. Morales

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  1. Jie Liu
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Correspondence to Peter H. Backx.

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J. Liu and K.-H. Kim contributed equally to this work.

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Liu, J., Kim, KH., London, B. et al. Dissection of the voltage-activated potassium outward currents in adult mouse ventricular myocytes: I to,f, I to,s, I K,slow1, I K,slow2, and I ss . Basic Res Cardiol 106, 189–204 (2011). https://doi.org/10.1007/s00395-010-0134-z

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