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September 29, 2020
How anesthetics and benzodiazepine affect the brain differently
At a Glance
- Researchers identified how anesthetic and benzodiazepine drugs change a brain receptor’s shape, providing a new level of detail in understanding anesthesia.
- The results suggest ways to design more tailored anesthetic drugs in the future.
General anesthetics are used to put patients to sleep before surgical procedures. Many general anesthetics work primarily through a brain protein called the GABAA receptor. Benzodiazepines, another widely prescribed type of sedative, also act through this same receptor. However, benzodiazepines have a wide range of calming effects. Low doses can make you feel sedated and high doses can act as an anesthetic. They’re often used to treat anxiety, epilepsy, and insomnia.
The GABAA receptor forms a channel through cell membranes. The molecule in the brain that activates the receptor is called GABA. It causes the channel to open, letting in ions to quiet the brain cells’ activity. But how anesthetics and benzodiazepines can have different sedating effects hasn’t been clearly understood.
To better understand how these drugs interact with the GABAA receptor, a research team led by Drs. Jeong Joo Kim and Ryan Hibbs from the University of Texas Southwestern Medical Center mapped the receptor’s atomic structure while it interacted with three different anesthetic drugs (phenobarbital, etomidate, and propofol) and a commonly used benzodiazepine drug called diazepam. The team also mapped the receptor’s interactions with a drug used to treat benzodiazepine overdoses, called flumazenil.
The work was supported in part by NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and National Institute on Drug Abuse (NIDA). Results were published on September 2, 2020 in Nature.
Using a technique called cryogenic electron microscopy, or cryo-EM, the team froze and imaged the GABAA receptor while interacting with each individual drug. They mapped where each one bound to the receptor. They found that the anesthetic drugs and the benzodiazepine bound to the receptor at both distinct and overlapping sites.
The researchers also compared changes in the receptor’s shape when it interacted with each drug. When the anesthetic drugs bound the receptor, they stabilized the channel in a more open shape. This change makes it easier for GABA to open the channel and calm the activity of the brain cell.
Diazepam also shifted the receptor’s structure so the channel could be more easily opened, but to a lesser degree. Flumazenil destabilized the site where diazepam, etomidate, and propofol bind, suggesting how it may reverse the action of benzodiazepines and some general anesthetics.
“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,” Hibbs says. “This is now a launching point for the discovery of improved, more selective anesthetics.”
—by Tianna Hicklin, Ph.D.
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References: Shared structural mechanisms of general anaesthetics and benzodiazepines. Kim JJ, Gharpure A, Teng J, Zhuang Y, Howard RJ, Zhu S, Noviello CM, Walsh RM Jr, Lindahl E, Hibbs RE. Nature. 2020 Sep;585(7824):303-308. doi: 10.1038/s41586-020-2654-5. Epub 2020 Sep 2. PMID: 32879488.
Funding: NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and National Institute on Drug Abuse (NIDA); Vetenskapsrådet VR; Knut and Alice Wallenberg Foundation; Welch Foundation.