NIH Research Matters
June 13, 2009
Alcohol’s Site of Action Revealed
People have used alcohol for thousands of years for its pleasant and intoxicating effects. A new study finally provides an explanation for how it produces these effects in the brain. The breakthrough could lead to new treatments for alcohol abuse and dependence.
Despite considerable research, an understanding of how alcohol affects the brain has remained elusive. A decade ago, researchers funded by NIH's National Institute on Alcohol Abuse and Alcoholism (NIAAA) identified a membrane channel in brain cells that's activated by ethanol, the type of alcohol found in alcoholic beverages. The channel, called G-protein-coupled 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 some other way.
Dr. Paul A. Slesinger and his colleagues at the Salk Institute recently solved the structure of a key portion of a molecule related to GIRK. They noticed that both it and a protein that allows fruit flies to sense alcohol have alcohol-binding sites similar to an area on GIRK. Funded by NIAAA and NIH's National Institute of General Medical Sciences (NIGMS), they set out to investigate whether ethanol binds GIRK at the suspected site.
The researchers systematically substituted different amino acids in the protein sequence of GIRK's potential alcohol binding "pocket." In the online edition of Nature Neuroscience on June 28, 2009, 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 scientists 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 approaches to treat alcohol abuse and dependence. For example, it might be possible to develop a drug that blocks alcohol from entering GIRK's binding pocket.
—by Harrison Wein, Ph.D.
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Editor: Harrison Wein, Ph.D.
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NIH Research Matters is a weekly update of NIH research highlights from the Office of Communications and Public Liaison, Office of the Director, National Institutes of Health.