| Anesthesiology

A Better Understanding of Anesthetics

GABAA, the Brain, and Potential “improved, more selective anesthetics

Newswise — ...UT Southwestern scientists have shown exactly how anesthetics attach to the GABAA receptor and alter its three-dimensional structure, and how the brain can tell the difference between anesthetics and the psychoactive drugs known as benzodiazepines – which also bind to the GABAA receptor. The findings were published online today in the journal Nature.

In 2018, study leader Ryan Hibbs, Ph.D.--an associate professor of neuroscience and biophysics at UTSW and senior author of the new paper--lab group detailed the first ever atomic structure of the GABAA receptor. In the new study, Hibbs and his colleagues looked again at the structure of the receptor in an environment more closely mimicking the cell, and this time while it was being bound by one of three different anesthetics – phenobarbital, etomidate, and propofol – as well as the benzodiazepine drug diazepam, or Valium, which is used to treat anxiety disorders, and the drug flumazenil, which can treat benzodiazepine overdoses.

The team discovered that both general anesthetics and diazepam could bind to multiple places on the GABAA molecule. One site – dubbed the “benzo site” in earlier research – was unique to the diazepam. But another site overlapped between the two drug types. When diazepam was present at high enough doses, it bound to this site that was more often used by the anesthetics. This observation could explain why high doses of benzodiazepines like diazepam can have anesthetic-like effects. The researchers also found differences among the general anesthetics; phenobarbital, for instance, bound to a place on GABAA that neither etomidate nor propofol attached, and seemed to be less choosy about where it bound.

“The fact that there are differences in the binding sites gives us some hope that we might be able to create more specific molecules that bind to only one site on the GABAA receptor,” says Hibbs, an Effie Marie Cain Scholar in Medical Research. “This is now a launching point for the discovery of improved, more selective anesthetics.”


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