Based on work in human cells, activation of the KCNK2 (TREK1) potassium channel by inhaled anesthetic has been shown to be PLD2-dependent; blocking PLD2's catalytic activity blocks the effects of anesthetics on the channel. PLD2 encodes a phospholipase that localizes to lipid rafts within the cell membrane. Pursuing a hypothesis that anesthetics could activate KCNK2 indirectly by disruption of lipid rafts, the affect of anesthetic treatment specifically on GM1 rafts was assessed. It was shown that treatment of cells with anesthetic results in an increase in the amount and size of GM1 rafts and in disruption of PLD2 association with lipid rafts.
Making use of Drosophila as a whole animals model of this process, it was shown that animals homozygous for a loss-of-function allele of Dmel\Pld are less susceptible to sedation by chloroform vapor. In the whole brain of adult flies, microscopic examination indicates that anesthesia disrupts lipid rafts in a manner similar to that observed in human cells.
The human Hsap\PLD2 gene has been introduced into flies, but has not been used in the context of this model.
See also the FlyBase chemical reports for chloroform (FBch0001062), diethyl ether (FBch0000882), isoflurane (FBch0000347), methyl beta-cyclodextrin (FBch0001072), propofol (FBch0000881), xenon (FBch0001060), ethanol (FBch0000064).
[updated Mar. 2024 by FlyBase; FBrf0222196]
Phospholipases are a group of enzymes that hydrolyze phospholipids into fatty acids and other lipophilic molecules; the protein encoded by PLD2 catalyzes the hydrolysis of phosphatidylcholine to phosphatidic acid and choline. The PLD2 protein localizes to the peripheral membrane and may be involved in cytoskeletal organization, cell cycle control, transcriptional regulation, and/or regulated secretion. [Gene Cards, PLD2; 2021.06.26]
KCNK2 (TREK1) is a 2-pore-domain background potassium channel expressed throughout the central nervous system. It is opened by polyunsaturated fatty acids, lysophospholipids, and volatile anesthetics (Heurteaux et al., 2004; pubmed:15175651).[from MIM:603219; 2021.06.26]
Many to one: 2 human genes to 1 Drosophila gene.
High-scoring ortholog of human PLD2 and PLD1 (1 Drosophila to 2 human). Dmel\Pld shares 36-38% identity and 50-52% similarity with the human genes.
