Certain proteins found in the human brain have long been known to be critical to controlling how brain cells communicate with each other. So-called GABA A receptors are proteins that control the flow of ions into and out of cells. As they play such a vital role in how neurons slow down or stop firing, they have become the targets of many drugs for conditions such as epilepsy, anxiety, depression and insomnia.
Yet due to technical limitations and the delicate nature of studying human brain tissue, scientists have lacked a complete picture of how GABA A receptors, and their 19 subunits, come together to carry out their functions.
Researchers at the University of California San Diego and University of Texas Southwestern Medical Center have for the first time constructed a detailed structural map of GABA A receptors in the human brain, revealing how they assemble and how drugs bind to them. Their findings were published on January 22, 2025 in the journal Nature .
“These receptors are targeted by many drugs for a variety of conditions, and by studying receptors directly from human brains, this research provides new insights into their exact structure, including how they interact with specific drugs,” said study senior author Professor Ryan Hibbs of UC San Diego’s School of Biological Sciences.
Due to the technical challenges of studying human brain samples, scientists had relied on information about GABA A receptors using studies from simplified systems, rather than direct examination of the protein in brain tissue. Jia Zhou, a postdoctoral scholar in the Department of Neurobiology, Hibbs and fellow research team members were able to overcome these obstacles with direct examinations of human GABA A receptors.
Samples were collected with full consent from patients undergoing surgery to treat epilepsy. These surgeries removed small portions of brain tissue that were already being taken out for medical purposes.
The tissue samples were then analyzed at UC San Diego in the Hibbs lab and the recently opened Goeddel Family Technology Sandbox, which features advanced cryo-electron microscopy (cryo-EM) instruments. Cryo-EM flash-cools tissue in a process that “freezes” samples in place and results in new ways to visualize intricate details not possible through other means. The researchers also used electrophysiology to measure how GABA A receptors function and respond to drugs.
The results allowed the scientists to create a detailed map of GABA A receptors, revealing how they assemble together and how drugs bind to them. The cryo-EM data allowed the researchers to construct 3-D structural models of 12 GABA A receptor subunit assemblies, which revealed the great variety of ways the subunits come together to make the receptors, as well as new drug mechanisms that may be relevant to treating epilepsy.
The new information paves a path to understanding why certain drugs work effectively or fail when treating neurological disorders. The researchers reported that they have already discovered novel functions for two epilepsy drugs previously not known to act on GABA A receptors.
“This research helps explain how the brain’s ‘brakes’ work — how neurons slow down or stop firing,” said Zhou, the paper’s lead author. “By understanding this process, scientists can create better treatments for conditions like epilepsy, anxiety and insomnia, ultimately improving the lives of millions of people.”
The researchers are now studying how the different subunit combinations affect receptor functions across various brain regions, as well as investigating the design of new drugs that more precisely target these receptors. They also plan to expand the studies into patients with specific neurological conditions for possible customized therapies.
Nature
Experimental study
People
Resolving native GABAA receptor structures from the human brain
22-Jan-2025