Recent advancements in cryogenic electron microscopy (cryo-EM) have led scientists to uncover vital mechanisms behind how glutamate, a key neurotransmitter, activates brain receptors. This groundbreaking research, spearheaded by experts at Johns Hopkins Medicine, offers promising insights into the development of new neurological treatments aimed at conditions such as epilepsy and certain intellectual disabilities.
Understanding how brain cells communicate through chemical signals is crucial for neuroscience. The research team utilized a highly specialized microscope to capture intricate images of how glutamate activates an essential channel, known as the AMPA receptor. This channel allows charged particles to flow into cells, creating electrical signals that facilitate communication between neurons. Dr. Edward Twomey, Ph.D., assistant professor of biophysics and biophysical chemistry at Johns Hopkins University School of Medicine, emphasizes the importance of these chemical communications, stating, “Neurons are the cellular foundation of the brain, and the ability to experience our environment and learn depends on chemical communications between neurons.”
The research focused on the detailed movements of AMPA receptors at a molecular level, utilizing a powerful cryo-electron microscope located at Johns Hopkins University. The team discovered that studying cell samples at normal body temperature (37 degrees Celsius or 98.6 degrees Fahrenheit) enhanced the activity of AMPA receptors and their interaction with glutamate, thereby increasing the chances of capturing their operational processes in cryo-EM images.
To conduct the study, researchers purified AMPA receptors from lab-grown human embryonic cells, which are widely used in neuroscience research. After heating the receptors to body temperature and exposing them to glutamate, the receptors were immediately flash-frozen for analysis. The resulting cryo-EM images revealed how glutamate acts as a "key" that opens the AMPA receptor channel, allowing charged particles to flow freely into the cell.
Dr. Twomey’s previous investigations have shown that certain drugs, like perampanel, function as inhibitors by blocking the AMPA receptor channel, thus reducing neuronal activity associated with epilepsy. The new findings from this study could pave the way for developing novel drugs that selectively bind to AMPA receptors, providing the potential to either activate or inhibit these crucial signaling pathways in brain cells. “With each new finding, we are figuring out each of the building blocks that enable our brains to function,” says Twomey.
This significant study, published on March 26 in the esteemed journal Nature, was conducted in collaboration with scientists from UTHealth Houston and received funding from the National Institutes of Health (R35GM154904, R35GM122528), the Searle Scholars Program, and the Diana Helis Henry Medical Research Foundation. The full reference for the study is: “Glutamate gating of AMPA-subtype iGluRs at physiological temperatures” by Anish Kumar Mondal, Elisa Carrillo, Vasanthi Jayaraman, and Edward C. Twomey.
As researchers continue to explore the intricacies of glutamate and its role in neuronal communication, the potential for innovative treatments for neurological disorders becomes increasingly promising.
