title: Regulation of the Mechano-Gated K2P Channel TREK-1 by Membrane Phospholipids.
abstract: This chapter discusses the regulation of the mechano-gated K(2P) channel, TREK-1 by membrane phospholipids. TREK-1 (KCNK2 or K2P2.1) is a polymodal K(+) channel that is activated by membrane stretch, intracellular acidosis, heat, and cellular lipids, such as arachidonic acid (AA). Phospholipids, including PIP2, exert a dual dose-dependent effect on TREK-1. Low concentrations transform the mechanogated K(+) channel TREK-1 into a leak K(+) channel. The phospholipid-sensing domain is a positively charged cluster in the proximal C-terminal domain. This region also encompasses the proton sensor E306 that is required for the activation of TREK-1 by cytosolic acidosis. Protonation of E306 increases channel-phospholipid interaction leading to TREK-1 opening without direct-mechanical stimulation. At higher concentrations, intracellular phospholipids inhibit channel activation by stretch, intracellular acidosis, and AA. Binding endogenous negative inner leaflet phospholipids with polylysine reduces the inhibition and reveals channel stimulation by exogenous intracellular phospholipids. Both stimulatory and inhibitory effects are observed with phosphatidylinositol (PI), phosphatidylethanolamine (PE), phosphatidylserine (PS), and phosphatidic acid (PA), but not diacylglycerol (DG), suggesting that the phosphate at position 3 is required, although the net charge is not critical. Membrane phospholipids, including PIP2, are major regulators of TREK-1 channel activity.
authors.affiliation: Institut de Genomique Fonctionnelle, UPR 2580 CNRS, F-34094 Montpellier cedex 05, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Chemin
authors.affiliation: Institut de Pharmacologie Moléculaire et cellulaire, UMR 6097 CNRS, 06560 Valbonne, France.
authors.forename: Amanda Jane
authors.initials: AJ
authors.lastname: Patel
authors.affiliation: Laboratoire de Neurophysiologie Cellulaire, Faculte de Medecine, UMR 6150 CNRS, 13916 Marseille Cedex 20, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Delmas
authors.affiliation: The Department of Physiology and Biophysics, Center for Single Molecule Biophysics, SUNY at Buffalo, Buffalo, New York 14214.
authors.forename: Frederick
authors.initials: F
authors.lastname: Sachs
authors.affiliation: Institut de Pharmacologie Moléculaire et cellulaire, UMR 6097 CNRS, 06560 Valbonne, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Lazdunski
authors.affiliation: Institut de Pharmacologie Moléculaire et cellulaire, UMR 6097 CNRS, 06560 Valbonne, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Honore