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Intracellular activation of full-length human TREK-1 channel by hypoxia, high lactate, and low pH denotes polymodal integration by ischemic factors

  • Ion channels, receptors and transporters
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Abstract

TREK-1, a two-pore domain potassium channel, responds to ischemic levels of intracellular lactate and acidic pH to provide neuroprotection. There are two splice variants of hTREK1: the shorter splice variant having a shorter N-terminus compared with the full-length hTREK1 with similar C-terminus sequence that is widely expressed in the brain. The shorter variant was reported to be irresponsive to hypoxia—a condition attributed to ischemia, which has put the neuroprotective role of hTREK-1 channel into question. Since interaction between N- and C-terminus of different ion channels shapes their gating, we re-examined the sensitivity of the full-length as well as the shorter hTREK-1 channel to intracellular hypoxia along with lactate. Single-channel data obtained from the excised inside-out patches of the full-length channel expressed in HEK293 cells indicated an increase in activity as opposed to a decrease in activity in the shorter isoform. However, both the isoforms showed an increase in activity under combined hypoxia, 20mM lactate, and low pH 6 condition, albeit with subtle differences in their individual actions, confirming the neuroprotective role played by hTREK-1 irrespective of the differences in the N-terminus among the splice variants. Furthermore, E321A mutant that disrupts the interaction of the C-terminus with the membrane showed a decrease in activity with hypoxia indicating the importance of the C-terminus in the hypoxic response of the full-length hTREK-1. We propose an increase in activity of both the splice variants of hTREK-1 in combined hypoxia, high lactate, and low pH conditions typically associated with ischemia provides neuroprotection.

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Data availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restriction.

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Acknowledgements

We thank Prof. Steve A.N Goldstein of Yale University and Dr. Delphine Bichet of IPMC, Nice, France, for kindly donating pRAT-hTREK-1 plasmid and pIRES2-hTREK1a plasmids respectively.

Funding

The research was funded by the Department of Biotechnology, Ministry of Science and Technology, DBT-IISc Partnership Program for Advanced Research in Biological Sciences and Bioengineering. This work was also supported by Department of Science and Technology (DST)- Innovation in Science Pursuit for Inspired Research (INSPIRE) fellowship to S.M.

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  1. Molecular Biophysics Unit, Indian Institute of Science, Bangalore, Karnataka, 560012, India

    Sourajit Mukherjee & Sujit Kumar Sikdar

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  1. Sourajit Mukherjee
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  2. Sujit Kumar Sikdar
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Contributions

S.M and S.K.S designed the experiments and S.M performed the single-channel inside-out electrophysiology and performed data analysis. S.M wrote the manuscript while S.K.S supervised the project and provided essential inputs in writing the manuscript.

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Correspondence to Sujit Kumar Sikdar.

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Mukherjee, S., Sikdar, S.K. Intracellular activation of full-length human TREK-1 channel by hypoxia, high lactate, and low pH denotes polymodal integration by ischemic factors. Pflugers Arch - Eur J Physiol 473, 167–183 (2021). https://doi.org/10.1007/s00424-020-02471-5

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  • DOI: https://doi.org/10.1007/s00424-020-02471-5

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