Oct. 1, 1997 After 155 years of searching, researchers have identified a small region on the surface of nerve cells that may be essential for the actions of inhaled anesthetics, opening a door to rational design of new pain medications.
The same site may be responsible for some of the depressive effects of alcohol and could provide crucial insights into the genetics of alcohol addiction.
The finding is reported by scientists from the University of Chicago Medical Center, the University of Colorado at Denver, and the University of Pennsylvania in the September 25 issue of Nature.
"For the first time, this allows us to begin the process of designing and synthesizing new anesthetics based on where and how they work rather than on serendipity and sheer dumb luck," said Neil Harrison, Ph.D., associate professor of anesthesia and critical care at the University of Chicago and director of the study, which was carried out in collaboration with Adron Harris (UC Denver) and colleagues Eric Greenblatt at Pennsylvania and John Mihic, now at Wake Forest University.
"In the long term," adds Harrison, "it should result in safer, more potent medications with far fewer side effects."
"Although one cannot be 100-percent certain that the binding sites themselves have been identified, this work represents an impressive and important step forward in understanding how these remarkable drugs work," said Nick Franks, Ph.D., head of the biophysics section at Imperial College of Science, Technology and Medicine, London, and a leader in the field. Franks and colleague William R. Lieb authored a News and Views in the same issue, putting the finding in perspective.
Knowing where anesthetics act would also speed the development of "antagonists," drugs that could rapidly reverse the effects of an anesthetic. Such antagonists, for example, could render a patient immediately wide awake and alert after surgery.
"This is a very important finding," said Alison Cole, Ph.D., Program Director at the National Institute of General Medical Sciences. "It provides the first structural basis for the sensitivity of anesthetics, a crucial tool for understanding how these drugs work and ultimately designing better ones."
Despite more than a century and a half of use--since January, 1842, when William Clarke first administered ether to help dentist Elijah Pope remove a tooth--no one has been able to demonstrate exactly how general anesthesia produces its effects. The traditional view was that anesthetics acted in a very nonspecific way, oozing into cell membranes to deactivate nerve cells. More recently, scientists have searched for more explicit targets, proteins on the surface of selected nerve cells.
A few years ago, the two labs in Chicago and Denver demonstrated that clinically relevant concentrations of inhaled anesthetics and alcohol enhanced the effects of a neurotransmitter called GABA (gamma-aminobutyric acid) and its close relative glycine.
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 about 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.
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