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A Singular Role of IK1 Promoting the Development of Cardiac Automaticity during Cardiomyocyte Differentiation by IK1 –Induced Activation of Pacemaker Current

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Abstract

The inward rectifier potassium current (IK1) is generally thought to suppress cardiac automaticity by hyperpolarizing membrane potential (MP). We recently observed that IK1 could promote the spontaneously-firing automaticity induced by upregulation of pacemaker funny current (If) in adult ventricular cardiomyocytes (CMs). However, the intriguing ability of IK1 to activate If and thereby promote automaticity has not been explored. In this study, we combined mathematical and experimental assays and found that only IK1 and If, at a proper-ratio of densities, were sufficient to generate rhythmic MP-oscillations even in unexcitable cells (i.e. HEK293T cells and undifferentiated mouse embryonic stem cells [ESCs]). We termed this effect IK1-induced If activation. Consistent with previous findings, our electrophysiological recordings observed that around 50% of mouse (m) and human (h) ESC-differentiated CMs could spontaneously fire action potentials (APs). We found that spontaneously-firing ESC-CMs displayed more hyperpolarized maximum diastolic potential and more outward IK1 current than quiescent-yet-excitable m/hESC-CMs. Rather than classical depolarization pacing, quiescent mESC-CMs were able to fire APs spontaneously with an electrode-injected small outward-current that hyperpolarizes MP. The automaticity to spontaneously fire APs was also promoted in quiescent hESC-CMs by an IK1-specific agonist zacopride. In addition, we found that the number of spontaneously-firing m/hESC-CMs was significantly decreased when If was acutely upregulated by Ad-CGI-HCN infection. Our study reveals a novel role of IK1 promoting the development of cardiac automaticity in m/hESC-CMs through a mechanism of IK1-induced If activation and demonstrates a synergistic interaction between IK1 and If that regulates cardiac automaticity.

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Acknowledgments

We are grateful to Dr. Jill Dunham for editorial assistance. This work was supported by the Start-up Fund from The MetroHealth System (to J.D.F.) and grants from the American Heart Association-13SDG14580035 (to J.D.F.), the Research Grant Council (TRS T13-706/11 to R.A.L.) and the National Institutes of Health (NIH)-R01HL096962 (to I.D.), NIH-R21HL123012 (to K.R.L.).

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  1. Yu Sun and Valeriy Timofeyev contributed equally to this study.

Authors and Affiliations

  1. Department of Medicine, Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, 2500 Metrohealth Drive, Rammelkamp 650, Cleveland, OH, 44109, USA

    Yu Sun, Adrienne Dennis, Emre Bektik, Xiaoping Wan, Kenneth R. Laurita, Isabelle Deschênes & Ji-Dong Fu

  2. Department of Internal Medicine, University of California, Davis, CA, USA

    Valeriy Timofeyev

  3. Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Japan

    Emre Bektik

  4. Dr. Li Dak-Sum Center for Regenerative Medicine, University of Hong Kong, The Hong Kong Jockey Club Building for Interdisciplinary Research, LB 5-06, 5 Sassoon Road, Pokfulam, Hong Kong

    Ronald A. Li

  5. Ming-Wai Lau Center for Regenerative Medicine, Karolinska Institutet, Solna, Sweden

    Ronald A. Li

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  1. Yu Sun
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Correspondence to Ronald A. Li or Ji-Dong Fu.

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Sun, Y., Timofeyev, V., Dennis, A. et al. A Singular Role of IK1 Promoting the Development of Cardiac Automaticity during Cardiomyocyte Differentiation by IK1 –Induced Activation of Pacemaker Current. Stem Cell Rev and Rep 13, 631–643 (2017). https://doi.org/10.1007/s12015-017-9745-1

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