Researchers Discover Alcohol Trigger Site in Brain
Ethanol, the alcohol found in beverages like beer, wine, and hard liquor, is known to alter the communication between brain cells. Paul A. Slesinger, PhD., an associate professor in the Peptide Biology Laboratory at the Salk Institute, said that there has been a lot of interest in how alcohol acts in the brain. “One of several views held is that ethanol works by interacting directly with ion channel proteins, but there were no studies that visualized the site of association,” he said.
Slesinger and his team showed that alcohol indeed directly interacts with a specific nook within a channel protein. This ion channel plays a key role in several brain functions associated with drug abuse and seizures. Previous research by Slesinger and his group focused on the neural function of these ion channels, called GIRK channels (G-protein-activated inwardly rectifying potassium channels). GIRK channels open up during periods of chemical communication between neurons and dampen the signal, creating a “short circuit” in the brain.
"When GIRKs open in response to neurotransmitter activation, potassium ions leak out of the neuron, decreasing neuronal activity," said UCSD Biology graduate student and first author Prafulla Aryal. Alcohol had been previously shown to open up GIRK channels, but it was not known whether this was a direct effect or whether it was a by-product of other molecular changes in the cell.
Using this protein structure, it may be possible to develop a drug that antagonizes the actions of alcohol to treat alcoholism. Finding a new drug that activates GIRK channels may also “dampen overall neuronal excitability in the brain and perhaps provide a new tool for treating epilepsy,” Slesinger said.
To gain more insight into how alcohol works in the brain, Slesinger, Aryal, and others teamed up to determine whether tiny pockets found in a high-resolution, three-dimensional structure of a potassium channel were actually the sites of alcohol action in GIRK channels. They confirmed this when amino acid substitutions denied alcohol molecules access to the potential alcohol binding site and alcohol could no longer effectively activate the channel.
The team further established that this pocket is also a trigger point for channel activation since G protein activation was also altered. “We believe alcohol hijacks the intrinsic activation mechanism of GIRK channels and stabilizes the opening of the channel,” said Aryal. Slesinger added that “alcohol may accomplish this by lubricating the activation gears of the channel.”