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Kir2.1 channels set two levels of resting membrane potential with inward rectification

  • Ion channels, receptors and transporters
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Strong inward rectifier K+ channels (Kir2.1) mediate background K+ currents primarily responsible for maintenance of resting membrane potential. Multiple types of cells exhibit two levels of resting membrane potential. Kir2.1 and K2P1 currents counterbalance, partially accounting for the phenomenon of human cardiomyocytes in subphysiological extracellular K+ concentrations or pathological hypokalemic conditions. The mechanism of how Kir2.1 channels contribute to the two levels of resting membrane potential in different types of cells is not well understood. Here we test the hypothesis that Kir2.1 channels set two levels of resting membrane potential with inward rectification. Under hypokalemic conditions, Kir2.1 currents counterbalance HCN2 or HCN4 cation currents in CHO cells that heterologously express both channels, generating N-shaped current-voltage relationships that cross the voltage axis three times and reconstituting two levels of resting membrane potential. Blockade of HCN channels eliminated the phenomenon in K2P1-deficient Kir2.1-expressing human cardiomyocytes derived from induced pluripotent stem cells or CHO cells expressing both Kir2.1 and HCN2 channels. Weakly inward rectifier Kir4.1 or inward rectification-deficient Kir2.1•E224G mutant channels do not set such two levels of resting membrane potential when co-expressed with HCN2 channels in CHO cells or when overexpressed in human cardiomyocytes derived from induced pluripotent stem cells. These findings demonstrate a common mechanism that Kir2.1 channels set two levels of resting membrane potential with inward rectification by balancing inward currents through different cation channels such as hyperpolarization-activated HCN channels or hypokalemia-induced K2P1 leak channels.

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Abbreviations

HCN:

Hyperpolarization-activated cyclic nucleotide-gated cation channel

iPSC:

Induced pluripotent stem cells

I-V :

Current-voltage

Kir2.1:

Inward rectifier K+ channel subfamily 2 isoform 1

K2P1:

Two pore-domain K+ channel isoform 1

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Acknowledgements

We thank Steven A. Siegelbaum, Juliane Stieber, and Catherine Proenza for providing HCN plasmids and Stephen J. Tucker for providing rat Kir4.1 plasmids.

Funding

This work was supported by the National Institute of General Medical Sciences, NIH (R01GM102943) and the National Natural Science Foundation of China (81370296, 81370297, and 81570303).

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Author notes

  1. Kuihao Chen and Dongchuan Zuo contributed equally to this work.

Authors and Affiliations

  1. Department of Biological Sciences, University at Albany, State University of New York, Albany, NY, 12222, USA

    Kuihao Chen, Dongchuan Zuo & Haijun Chen

  2. Department of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China

    Zheng Liu

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  1. Kuihao Chen
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  2. Dongchuan Zuo
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Contributions

HC, DZ, KC, and ZL designed the research; HC, DZ, and KC analyzed data; DZ and KC performed the research; and HC, DZ, and KC wrote the paper.

Corresponding author

Correspondence to Haijun Chen.

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Chen, K., Zuo, D., Liu, Z. et al. Kir2.1 channels set two levels of resting membrane potential with inward rectification. Pflugers Arch - Eur J Physiol 470, 599–611 (2018). https://doi.org/10.1007/s00424-017-2099-3

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