INTOXICATING STUFF

Designer proteins reveal how drink goes to your head

ALCOHOL may make you tipsy by slipping into protein pockets on the surfaces
of nerve cells, say biologists in the US. If true, we could soon have a
clutch of new treatments for alcoholism or drugs that prevent hangovers.

For years, scientists have known that medium-sized alcohol molecules tend
to have a greater effect than smaller ones. Propanol, which has three
carbon atoms, can knock you out faster than ethanol, which has only two.
But alcohols with more than seven to ten carbons in a chain carry less
punch.

Neil Harrison at the University of Chicago, Adron Harris of the University
of Colorado in Denver and their colleagues made mutant versions of two
proteins, the glycine receptor and the GABA receptor, which regulate the
flow of ions into neurons. Alcohol makes these receptors admit excessive
amounts of chloride ions to the cell, resulting in less neural activity
(New Scientist, Science, 24 August 1991, p 21). But no one has been sure
exactly how alcohol opens these ion floodgates.

One possibility is that the alcohol binds directly to the receptors. So
Harrison and Harris changed the size of a pocket in the protein into which
alcohol might fit by replacing amino acids lining the pocket with smaller
or larger ones. "If this is really the binding site for ethanol, you should
be able to get bigger alcohols to fit," Harris says.

When the mutant proteins were expressed in frog eggs, the researchers found
that receptors with bigger pockets were sensitive to alcohols with more
than ten carbons, allowing ions to rush in. Smaller pockets lowered the
alcohol cutoff size. In the current Proceedings of the National Academy of
Sciences (vol 95, p 6504), they conclude that the alcohols are slipping
directly into the crevices on the receptors.

Teasing out the details of alcohol's interaction with neural receptors
could be very useful, comments lan Diamond, who studies the biological
effects of alcohol at the University of California at San Francisco.
Alcohol probably binds to many different receptors causing different
physiological effects, and understanding these interactions could lead to
drugs that block only the undesirable ones. Such drugs could disrupt
alcoholic cravings or even prevent hangovers. "But that's still purely
theoretical," he says.

Checked-by: (Joel W. Johnson)