Specific protein receptors in the brain are crucial for regulating how neurons slow down or cease their activity, making them key targets for numerous disorders. Researchers have now developed an intricate structural map of these receptors in the human brain, providing insights into their assembly and the way drugs interact with them.
Certain proteins present in the human brain are recognized for their essential role in facilitating communication between brain cells. The GABAA receptors are one type of protein that manages the movement of ions in and out of cells. Because they are instrumental in how neurons diminish or halt their firing, they have become focal points for various medications used to treat conditions like epilepsy, anxiety, depression, and insomnia.
However, scientists have previously struggled to gain a comprehensive understanding of how GABAA receptors, along with their 19 subunits, function and align due to technical barriers and the sensitive nature of human brain tissue research.
A team of researchers from the University of California San Diego and the University of Texas Southwestern Medical Center has now created for the first time a detailed structural map of GABAA receptors in the human brain, unveiling insights into their assembly and how drugs attach to them. Their research findings were published on January 22, 2025, in the journal Nature.
“As many drugs target these receptors for various conditions, studying them directly from human brains has offered fresh perspectives on their precise structure and interactions with specific medications,” stated Professor Ryan Hibbs, the senior author of the study from UC San Diego’s School of Biological Sciences.
Prior to this, scientists relied on studies from simplified systems rather than direct analysis of the receptors in human brain samples due to the challenges associated with studying them. However, Jia Zhou, a postdoctoral scholar in the Department of Neurobiology, and her fellow researchers managed to navigate these challenges by directly examining human GABAA receptors.
The tissue samples were obtained with full consent from patients who were undergoing surgery for epilepsy treatment, where small sections of brain tissue were removed for medical purposes.
These samples were then analyzed in UC San Diego’s Hibbs lab and the recently launched Goeddel Family Technology Sandbox, which houses advanced cryo-electron microscopy (cryo-EM) equipment. This cryo-EM technique fast-cools the tissue, “freezing” the samples in place and offering unique visualization capabilities for intricate details that other methods cannot achieve. Additionally, electrophysiology assessments were employed to understand how GABAA receptors operate and react to medications.
The team’s results enabled them to create a detailed representation of GABAA receptors, illustrating how they come together and how drugs securely bind to them. Utilizing cryo-EM data, the researchers constructed 3D structural models of 12 GABAA receptor subunit assemblies, demonstrating the diverse ways in which the subunits can combine to form the receptors and revealing new drug action mechanisms pertinent to epilepsy treatment.
This new knowledge helps clarify why particular drugs are effective or ineffective when treating neurological disorders. The researchers announced they had already identified novel functions for two epilepsy medications that were previously unknown to interact with GABAA receptors.
“This research sheds light on how the brain’s ‘brakes’ function—specifically, how neurons can slow down or stop their activity,” explained Zhou, the lead author of the paper. “By grasping this process, scientists can develop improved treatments for epilepsy, anxiety, and insomnia, ultimately enhancing the quality of life for millions.”
Moving forward, the researchers are examining how the various combinations of subunits influence receptor functions across different brain regions and are working on designing new drugs that target these receptors more precisely. They also intend to broaden their studies to include patients with specific neurological conditions for possible customized treatment options.
