Abstract
TREK-1 is an unconventional K+ channel that is activated by both physical and chemical stimuli. In this study, we show that the inner leaflet membrane phospholipids, including PIP2, exert a mixed stimulatory and inhibitory effect on TREK-1. Intra-cellular phospholipids inhibit basal channel activity and activation by membrane stretch, intra-cellular acidosis and arachidonic acid. However, binding of endogenous negative inner leaflet phospholipids with poly-lysine reduces inhibition and reveals channel stimulation by exogenous intra-cellular phospholipids. A similar effect is observed with PI, PE, PS and PA, unlike DG, demonstrating that the phosphate at position 3 is required although the global charge of the molecule is not critical. Inhibition depends on the distal C-terminal domain that conditions channel mechano-sensitivity, but is independent of the positively charged PIP2 stimulatory site in the proximal C-terminal domain. This is, to our knowledge, the first report of an ion channel dually regulated by membrane phospholipids.
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Acknowledgements
This work was supported by the CNRS, the FRM, l’ARC, la Ligue contre le cancer, the Fondation Paul Hamel and the ANR COD 2005. Martine Jodar is acknowledged for the expert technical assistance.
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Chemin, J., Patel, A.J., Duprat, F. et al. Up- and down-regulation of the mechano-gated K2P channel TREK-1 by PIP2 and other membrane phospholipids. Pflugers Arch - Eur J Physiol 455, 97–103 (2007). https://doi.org/10.1007/s00424-007-0250-2
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DOI: https://doi.org/10.1007/s00424-007-0250-2