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

Mukherjee, S and Sikdar, SK (2020) Intracellular activation of full-length human TREK-1 channel by hypoxia, high lactate, and low pH denotes polymodal integration by ischemic factors. In: Pflugers Archiv European Journal of Physiology . (In Press)

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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. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature.

Item Type:	Journal Article
Publication:	Pflugers Archiv European Journal of Physiology
Publisher:	Springer Science and Business Media Deutschland GmbH
Additional Information:	copyright to this article belongs to Springer Science and Business Media Deutschland GmbH
Department/Centre:	Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited:	29 Oct 2020 11:41
Last Modified:	29 Oct 2020 11:41
URI:	http://eprints.iisc.ac.in/id/eprint/67030

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