Work

A Molecular Target for an Alcohol Chain-Length Cutoff

Year: 2018

Type: article

Abstract: Despite the widespread consumption of ethanol, mechanisms underlying its anesthetic effects remain uncertain. n -Alcohols induce anesthesia up to a specific chain length and then lose potency—an observation known as the “chain-length cutoff effect.” This cutoff effect is thought to be mediated by alcohol binding sites on proteins such as ion channels, but where these sites are for long-chain alcohols and how they mediate a cutoff remain poorly defined. In animals, the enzyme phospholipase D (PLD) has been shown to generate alcohol metabolites (e.g., phosphatidylethanol) with a cutoff, but no phenotype has been shown connecting PLD to an anesthetic effect. Here we show loss of PLD blocks ethanol-mediated hyperactivity in Drosophila melanogaster (fruit fly), demonstrating that PLD mediates behavioral responses to alcohol in vivo . Furthermore, the metabolite phosphatidylethanol directly competes for the endogenous PLD product phosphatidic acid at lipid-binding sites within potassium channels [e.g., TWIK-related K + channel type 1 (K2P2.1, TREK-1)]. This gives rise to a PLD-dependent cutoff in TREK-1. We propose an alcohol pathway where PLD produces lipid-alcohol metabolites that bind to and regulate downstream effector molecules including lipid-regulated potassium channels.

Source: Journal of Molecular Biology

DOI: 10.1016/j.jmb.2018.11.028