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Biological Chemistry

Under The Influence Of Ethanol: How Alcoholic Beverages Are Like Allosteric Drugs

by Carmen Drahl
November 23, 2009 | A version of this story appeared in Volume 87, Issue 47

HERE’S TO STRUCTURE

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Credit: Courtesy of S. J. Mihic
Butanol (green) binds at an allosteric site in the fruit fly protein LUSH.

Credit: Courtesy of S. J. Mihic
Butanol (green) binds at an allosteric site in the fruit fly protein LUSH.


COVER STORY

Under The Influence Of Ethanol: How Alcoholic Beverages Are Like Allosteric Drugs

Wherever there's a happy hour, there's allosteric modulation.

Although researchers are only beginning to understand how the ethanol in a keg of beer or a snifter of brandy works on a molecular level, they do know that it interacts with targets at allosteric sites, which are areas of a protein outside the site that binds the natural ligands. That knowledge may lead to new treatments for alcoholism.

"Ethanol is an unusual drug molecule—it's very small with little structural complexity, and we take it in quantities more like food than like a prescription," says R. Adron Harris, a pharmacologist at the University of Texas, Austin. Compared with a typical medication, the amount of alcohol that elicits biological effects is astronomical. A blood-alcohol concentration of 0.08%, the level that in many states classifies a person as legally drunk, equates to an ethanol concentration of 17 mM, whereas a typical drug acts at the nanomolar range. "To a pharmacologist, this is really strange," Harris says. "Everyone wondered how ethanol was working."

Until the 1980s, scientists thought that alcohol simply interacted with lipids, affecting the cell membrane's fluidity and nonspecifically altering how neurons functioned. People didn't think that a molecule as tiny as ethanol flooding receptors at high concentrations could have specific protein targets, Harris explains.

Biophysicists Nicholas P. Franks and William R. Lieb of Imperial College London played a big role in dispelling that idea. When they treated luciferase—the enzyme that fireflies use to make light—with alcohols, they found that the chemicals lowered the light output (Nature 1984, 310, 599). Since luciferase is lipid-free and not in the membrane yet is still sensitive to alcohols, that meant, in principle, that a protein could account for alcohol action, Harris says.

After that, "people started finding that some proteins were more sensitive to ethanol than others," says Richard W. Olsen, a pharmacologist at the University of California, Los Angeles. In particular, ethanol affects ion channels in the brain, including the glycine receptor, certain types of glutamate receptors, and the GABAA receptor, which is also the target of Valium, the blockbuster sedative that eventually was found to work through an allosteric mechanism. Ethanol boosts the activity of some receptors while lowering that of others. Other potential targets, picked up mostly in genetic studies, have varying amounts of support in the literature.

It was soon clear that ethanol works allosterically. Radioligand-binding assays conducted by several independent groups suggest that ethanol doesn't bind where naturally occurring ligands do, Harris says. Ethanol "doesn't activate receptors on its own—it is interfering with or changing natural functions," Olsen adds.

While researchers can demonstrate ethanol's allosteric mode of action, the specifics remain to be worked out. The most detailed explorations have been on GABAA and glycine receptors. With the help of a radiolabeled small molecule, Olsen's group proposed an allosteric site for ethanol action on the GABAA receptor (Proc. Natl. Acad. Sci. USA 2006, 103, 8540 and 8546).

Many researchers mutate receptors to identify ethanol-sensitive targets in the protein. Daryl L. Davies, a neuropharmacologist at the University of Southern California, searches for ethanol sites of action on glycine and GABAA receptors in just this way (J. Biol. Chem. 2009, 284, 27304).

To nail down sites of action, it would be handy to have X-ray crystal structures of putative protein targets of ethanol, but most are membrane-spanning proteins and so are tough to crystallize, Harris says. Among the scant data the field has to go on is a structure (shown) of butanol (green = carbon) bound to LUSH, a cheekily named protein in fruit flies that helps them avoid toxic concentrations of alcohols. When LUSH is mutated, flies throw caution to the wind, flocking to cognac and similarly strong spirits.

Most alcohol-addiction drugs work downstream of ethanol action or on ethanol metabolism, says Robert O. Messing, a neurologist and senior associate director of the University of California, San Francisco's Ernest Gallo Clinic & Research Center, a leading center for the study of substance abuse. If researchers could conclusively identify allosteric sites where ethanol exerts its effects, it might spur renewed drug discovery efforts for more direct-acting antialcoholism medications. The path ahead is not yet clear, but the potential to help the millions struggling with alcoholism keeps the field going.

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