| Autor: |
Mukherjee S; Molecular Biophysics Unit, Indian Institute of Science, Bangalore, Karnataka, 560012, India., Sikdar SK; Molecular Biophysics Unit, Indian Institute of Science, Bangalore, Karnataka, 560012, India. sks@iisc.ac.in. |
| Jazyk: |
angličtina |
| Zdroj: |
Pflugers Archiv : European journal of physiology [Pflugers Arch] 2021 Feb; Vol. 473 (2), pp. 167-183. Date of Electronic Publication: 2020 Oct 06. |
| DOI: |
10.1007/s00424-020-02471-5 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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