Unlike "excitatory" neurotransmitters such as
glutamate or acetylcholine, which convey signals from
nerve to nerve, GABA is an "inhibitory"
neurotransmitter.
It blocks signals by preventing nerve
cells from sending messages upstream to the brain.
GABA is the most important inhibitory
neurotransmitter in the brain; glycine plays a major
role in the lower brain stem and spinal cord.
"GABA
makes sense as a target because it does the right job
in the brain," said Harrison. "It depresses the
central nervous system. By enhancing GABA, these
drugs interrupt the processing of sensory
information, resulting in the unconsciousness and
amnesia we get with anesthetics."
In order to find the crucial Contact regions, the
researchers substituted small pieces of a different
receptor into the GABA and glycine receptors to see
which parts could be replaced without altering the
receptor's response to alcohols or anesthetics. They
found a small region of 45 amino-acids that was
necessary for these drugs to enhance the receptor's
effects.
Within this crucial region, two specific mutations,
made by molecular biologist Qing Ye, rendered the
receptors completely unresponsive to alcohol or
anesthetics, presumably by changing the way the
proteins folded. The researchers suspect that the
proteins fold up to form a pocket that serves as the
binding site for the drugs and have built a model of
its possible configuration. They have also begun to
develop transgenic mice with mutations in the GABA
receptor to verify that alterations in the protein
will alter the response to anesthesia or alcohol.
"We can't be absolutely certain that we have found
the binding site for anesthetics or alcohol until we
can crystallize the protein and determine its
structure," cautioned Harrison, "but this does tell
us that this region is crucial for the drugs'
effects."
The findings may also help unravel the complex
genetics of alcoholism. "Alcohol clearly affects
other receptors too," admits co-author R. Adron
Harris, Ph.D., of the University of Colorado Health
Sciences Center. The rewarding aspects of alcohol are
generally attributed to its effects on the
neurotransmitter dopamine, "but our guess is that the
less pleasant, depressive or sedative effects of
alcohol involve its effects on GABA," said Harris.
"People with mutations in the GABA receptor, who
don't experience the same downsides from alcohol, may
have fewer incentives to restrict their drinking."
A pilot study, looking for mutations within the
critical region in a human population including
alcoholics, is already underway. Harrison and
geneticist Edwin Cook, M.D., of the University of
Chicago, are working with alcoholism specialist John
Crayton, M.D., now at Loyola University Medical
Center.
The research published in Nature was supported by
grants from the National Institute of General Medical
Sciences, the National Institute on Alcohol Abuse and
Alcoholism, the Foundation for Anesthesia Education
and Research, and the Brain Research Foundation.
:: Back to "How the Body Responds to Alcohol" ::
Summary:
Researchers have identified a region on the surface
of nerve cells that may be essential for the actions
of anesthetics, opening a door to rational design of
new medications. The same site may be responsible for
the depressive effects of alcohol and could provide
insights into the genetics of addiction.
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