Researchers published the first atomic structure of a brain receptor bound to a drug used to reverse anesthesia and to treat sedative overdoses.
Many drugs - both legal and illegal - work on the GABAA receptor. Particularly well-known are the benzodiazepines, which are used for anesthesia during surgery and prescribed to treat epilepsy, anxiety, and insomnia, senior author said, adding that solving the structure of the receptor could someday lead to better treatments for those conditions.
The GABAA receptor binds to GABA (γ-aminobutyric acid), the major inhibitory, or calming, neurotransmitter in the adult brain. Dysfunction of the GABAA receptor is found in conditions marked by excessive excitation in the brain, such as epilepsy. In addition to the benzodiazepine class of sedatives, the GABAA receptor is a common target for barbiturates, anesthetics, and alcohol, senior author added. All of these drugs act on the brain by increasing the activity of the GABAA receptor, which in turn further dampens, or calms, brain activity.
The GABAA receptor has been notoriously resistant to X-ray crystallography. That method - long considered the gold standard of structural biology - requires the crystallization of proteins so that structures can be determined based on X-ray diffraction patterns.
The lead author in this study pursued the structure by crystallography and obtained crystals that diffracted X-rays very poorly. In parallel, the author worked to obtain the structure using cryo-electron microscopy (cryo-EM), which was ultimately successful. The results provide the first 3D atomic structures of the receptor bound to its neurotransmitter GABA and to the drug flumazenil, which is used to reverse anesthesia and to treat benzodiazepine overdoses.
The researchers devised methods to express and purify the human synaptic GABAA receptor from cells in flasks and used electrophysiological experiments, in combination with the structural information from cryo-EM, to test the effects on the receptor of the neurotransmitter GABA, a benzodiazepine (diazepam), and flumazenil. The receptor architecture reveals unique heteromeric interactions for this important class of inhibitory neurotransmitter receptor.
"We were able to define how GABA binds so selectively to the receptor and to explain why drugs like benzodiazepines and flumazenil - the agent that competes with those drugs at the same binding site to reverse their effects - act specifically on this receptor," the senior author said. "The implications are far-reaching for understanding mechanisms of drug binding and designing new drugs for diverse neurological conditions."
Structure of human GABAA receptor elucidated!
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