Although scientists can learn a lot from cell culture and animal models, they cannot truly substitute for all parts of the human body, especially the brain. But scientists have now used human brain tissue donated by epilepsy patients to study the structure of GABAA receptors. These receptors are crucial molecules that help control the movement of ions in and out of cells, a process that has many important impacts. As such, GABAA receptors have been the target of drugs aiming to treat a variety of issues including anxiety, depression, epilepsy, and insomnia. But we have had an inadequate understanding of this receptor. This new work, reported in Nature, helps fill some of the gaps in our knowledge.
This research has elucidated the structure of GABAA receptors, and the nineteen subunits they carry. It can also show how some drugs interact with this receptor.
The samples used in this study were collected from epilepsy patients who were undergoing surgery that removes bits of brain tissue. The researchers prepared the tissue and analyzed it with cryo-electron microscopy (cryo-EM), which can reveal the fine details of a molecule's structure while it is frozen in place. Twelve subunit assemblies were analyzed in three dimensions to see how the subunits form the receptor.
A technique called electrophysiology was also used to measure how drugs affected the function of GABAA receptors. This tool can measure electrical impulses in neurons.
This data can hopefully show why certain medications are effective or not in the treatment of various neurological diseases. The investigators have already used it to identify new functions for epilepsy drugs that have not been previously known to affect GABAA receptors.
"This research helps explain how the brain's brakes work—how neurons slow down or stop firing," said lead study author Jia Zhou, a postdoctoral researcher at the University of California, San Diego. "By understanding this process, scientists can create better treatments for conditions like epilepsy, anxiety and insomnia, ultimately improving the lives of millions of people."
Now, the investigators want to learn more about how the subunits are related to the function of the receptor in different parts of the brain. They also want to create new medications that aim for these subunits more directly, and could improve therapeutics for different neurological conditions. Eventually, they hope to treat patients with more personalized drugs.
Sources: University of California San Diego, Nature
