Activation Site of Alcohol Discovered
People have always known that alcohol effects the brain, but until know they’ve never understood how it works. A new study finally provides an explanation for how alcohol affects the brain, which could lead to new treatments for alcohol abuse and dependence.
Ten years ago, researchers funded by the National Institute on Alcohol Abuse and Alcoholism identified a membrane channel in brain cells that is activated by ethanol, the type of alcohol found in alcoholic beverages. The channel, called G-protein couple inwardly rectifying potassium channel (GIRK), is found on cells throughout the brain and plays a key role in brain function.
Studies since then have confirmed that alcohol exerts its effects in living animals, at least in part, through GIRK. However, scientists haven’t known whether alcohol interacts directly with GIRK or affects it in some other way.
Dr. Paul A. Slesinger and colleagues at the Salk Institute recently noticed that a molecule related to GIRK and a protein that allows fruit flies to sense alcohol have alcohol-binding sites similar to an area on GIRK. They systematically substituted different amino acids in the protein sequence of GIRK’s potential alcohol binding “pocket.”
They reported that amino acids with bulkier side chains reduced or eliminated ethanol’s ability to activate GIRK. In contrast, those with smaller side chains didn’t block the alcohol’s effect on GIRK. These experiments, combined with structural analyses, led the researchers to propose a model for how alcohol activates GIRK channels. At rest, the channels open and close, but alcohol binding stabilizes the open shape, leading to alcohol-activated currents in brain cells.
"We believe alcohol hijacks the intrinsic activation mechanism of GIRK channels and stabilizes the opening of the channel," says first author Prafulla Aryal.
Identifying the physical site that ethanol uses to exert its effect is an important step in developing new methods for treating alcohol abuse and dependence. For example, it might be possible to develop a drug that blocks alcohol from entering GIRK's binding pocket.