Alcohol is something of a paradox in that it’s able to act as both a stimulant and a sedative. Indeed, many people who have consumed alcohol have probably experienced this first hand, and in the same order — first alcohol creates a stimulated ‘buzzed’ feeling which is followed by sedation. Yet exactly how alcohol is able to create this initial ‘buzz’ is still not fully understood.
Now, researchers at the Scripps Research Institute in Florida have revealed how one of our own proteins enables alcohol to excite nerve cells.
Humans aren’t the only animals susceptible to alcohol intoxication, other animals – from mammals to insects – are also vulnerable. Among these is the humble fruit fly.
And just like humans, they also get ‘buzzed’ when they imbibe.
“They act just like people,” says Scott Hansen at Scripps Research Institute. “They start losing coordination. They literally get drunk.”
“With hyperactivity you see the flies run around more, and this is what we equate to being buzzed,” he says.
To gain a better understanding of this ‘buzzed’ state, Hansen and his colleagues took a closer look at an enzyme called phosopholipase D2 (PLD2) in fruit flies.
PLD2 was known to be involved in the biological response to anesthesia, so they wondered if it was involved in alcohol intoxication, too.
PLD2 is found throughout the nervous system, and its main job is to produce something called phosphatidic acid (PA) which plays a multitude of important roles in cell function and growth. When PLD2 makes PA, it has to bind a water molecule as part of the process, but if enough alcohol is present, water can get shoved out of the way. When this happens, PLD2 uses an alcohol molecule to make a metabolite called phosphatidylethanol (PEtOH) instead.
Hansen and his colleagues discovered that this leads to downstream problems. As PEtOH builds up, it starts interfering with the function of critical proteins on nerve cells, causing the nerves to become more excitable. This, in turn, causes hyperactivity.
When the researchers disabled the gene for the enzyme PLD2 in a group of fruit flies, those flies did not become hyperactive when they drank alcohol.
Hansen explains that this is the first time this particular biochemical pathway has been shown to play a role in alcohol sensitivity.
“It has definitely led to some different ways of thinking about alcohol intoxication at the molecular level,” he says. “Most scientists thought alcohol had a direct effect. Blocking the enzyme in flies shows that’s not likely true.”
He now wants to find out whether this enzyme and the molecule PEtOH also contribute to the sedative effect of alcohol.
Understanding the mechanisms by which alcohol interacts with our bodies could help scientists better understand intoxication and perhaps develop an antidote, says Hansen.
“Also, understanding this pathway could give insight as to why people use alcohol for pain management,” he adds.
Chung, H W et al (2018) A Molecular Target for an Alcohol Chain-Length Cutoff. Journal of Molecular Biology