Up- and down-regulation of the mechano-gated K(2P) channel TREK-1 by PIP (2) and other membrane phospholipids.
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 PIP(2), 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 PIP(2) 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.
Chemin
Jean
J
Institut de Génomique Fonctionnelle, UPR 2580 CNRS, 141 rue de la Cardonille, 34094, Montpellier cedex 05, France.
Patel
Amanda Jane
AJ
Duprat
Fabrice
F
Sachs
Frederick
F
Lazdunski
Michel
M
Honore
Eric
E
D000704:Analysis of Variance; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D015536:Down-Regulation / Q000502:physiology; D004594:Electrophysiology; D005260:Female; D005822:Genetic Vectors; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D015640:Ion Channel Gating / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000494:pharmacology*; D010743:Phospholipids / Q000494:pharmacology*; D024683:Potassium Channels, Tandem Pore Domain / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D011247:Pregnancy; D051381:Rats; D012672:Semliki forest virus / Q000235:genetics; D015854:Up-Regulation / Q000502:physiology
D019269:Phosphatidylinositol 4,5-Diphosphate; D010743:Phospholipids; D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1