Many drugs—whether legal or illegal—act on one of the most abundant and important neurotransmitter receptors in the brain: type A GABA receptor (GABAA receptor). Particularly well-known are benzodiazepines, which are used for anesthesia during surgery and for the treatment of epilepsy, anxiety, and insomnia. The resolution of the three-dimensional structure of this receptor may one day lead to the development of better ways to treat these diseases.

 

The GABAA receptor binds to gamma-aminobutyric acid (GABA), which is the major inhibitory or sedative neurotransmitter in the adult brain. In order to function properly, the brain needs to balance irritating signals and sedative signals. GABAA receptor dysfunction is found in diseases characterized by excessive excitation in the brain, such as epilepsy. In addition to the sedative benzodiazepines, the GABAA receptor is a common target for barbiturates, anesthetics, and alcohol. All of these drugs act on the brain by increasing the activity of the GABAA receptor, thereby further inhibiting brain activity.

 

 

It is well known that the three-dimensional structure of the GABAA receptor is difficult to resolve by X-ray diffraction crystal analysis. This method has long been considered the gold standard for structural biology. It requires protein crystallization so that the protein structure can be determined from the X-ray diffraction pattern.

 

In a new study, researchers from the University of Texas Southwestern Medical Center turned to cryo-electron technology (cryo-EM) for help. They successfully solved the three-dimensional structure of GABAA receptor binding to GABA and the drug flumazenil for the first time. The results of the study were published in the journal Nature, entitled “Structure of a human synaptic GABAA receptor.” The author of the paper is Dr. Ryan Hibbs, Assistant Professor of Neuroscience and Biophysics at the University of Texas Southwestern Medical Center. The first author of the paper is Dr. Shaotong Zhu, a postdoctoral researcher at Hibbs Laboratory.

 

These researchers used cells to express human synaptic GABAA receptors and purified them, and combined electrophysiological experiments with structural information obtained by cryo-EM technology to test the effect of diazepam (a benzodiazepine) and flumazenil on this GABAA receptor, in which flumazenil is used to reverse anesthesia and treat benzodiazepine overdose. Dr. Hibbs said, “We are able to determine how GABA selectively binds to this receptor, and explain why drugs such as benzodiazepines and flumazenil, which competitively acts on the same site to reverse the effects of benzodiazepines, specifically act on this receptor. This has profound implications for understanding drug binding mechanisms and designing new drugs for the treatment of a variety of neurological diseases.”

 

 

 

Reference

Shaotong Zhu, Colleen M. Noviello, Jinfeng Teng et al. Structure of a human synaptic GABAA receptor. Nature, Published online: 27 June 2018, doi:10.1038/s41586-018-0255-3