Epilepsy is a brain disorder characterized by seizures that occur due to deficits in communication between brain cells. This communication is mediated by the AMPA receptor, which lives on the surface of neurons. When the chemical glutamate attaches to these receptors, it triggers them to open and allows electrical signals to pass through brain cells.
However, in epilepsy, AMPA receptors can become overactive, leading to excess signaling that can cause seizures. To manage these symptoms, doctors often prescribe medications, such as the drug perampanel. Although it’s well-known that perampanel works by reducing AMPA receptor activity in the brain, the specifics of how this happens have remained largely a mystery—until now.
Epilepsy results from overactive communication between brain cells.
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Thanks to an innovative technique called cryo-electron microscopy, scientists can now better understand how perampanel works. Researchers at Johns Hopkins University used cryo-electron microscopy to take pictures of AMPA receptors and combined these images into a 3D reconstruction with the help of artificial intelligence.
What they discovered was fascinating: Normally, glutamate binds to AMPA receptors at four different positions called “binding sites”. Once glutamate sits in the binding sites, it pulls on strand-like portions of the receptor that open a “gate” to allow electricity to flow through. However, perampanel blocks two specific sites out of the four, which specifically prevents glutamate from interacting with the receptor. This prevents the bursts of rapid electrical activity that can lead to seizures.
This finding is a breakthrough in the development of epilepsy treatments. With this knowledge, scientists can create drugs that more effectively block AMPA receptors to improve seizure control. Scientists can more carefully design drugs that target those specific binding sites, or even explore the efficacy of drugs targeting other binding sites.
The applications of this research may also stretch beyond epilepsy—AMPA receptors are important for learning and memory. This means AMPA receptor-targeting drugs have the potential to treat a variety of brain conditions, such as Alzheimer’s disease, learning disabilities related to the hippocampus (a part of the brain) and memory, brain cancers such as glioblastoma, and even chronic pain resulting from damaged tissue or nerve injuries. With continued research, AMPA receptor-targeting drugs may open new doors for treating epilepsy and many other neurological disorders, improving the quality of life for millions of patients worldwide.
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