A “dormant” brain protein turns out to be a powerful switch

The proteins at the center of the research are known as delta-type ionotropic glutamate receptors, or GluDs. These proteins are known to play an important role in how neurons communicate with each other. According to the researchers, mutations in GluDs have been linked to psychiatric disorders, including anxiety and schizophrenia. Despite this connection, scientists have struggled for years to understand exactly how these proteins work, making it difficult to design treatments that could regulate their activity.

"This class of protein has long been thought to be sitting dormant in the brain," says Edward Twomey, Ph.D., assistant professor of biophysics and biophysical chemistry at the Johns Hopkins University School of Medicine. "Our findings indicate they are very much active and offer a potential channel to develop new therapies."

The study describing these findings was published in Nature.

Imaging Reveals How GluDs Function

To better understand GluDs, Twomey and his team used cryo-electron microscopy, an advanced imaging technique that allows scientists to visualize proteins in fine detail. Their analysis showed that GluDs contain an ion channel at their center. This channel holds charged particles that help the proteins interact with neurotransmitters (electrical signals that allow brain cells to communicate with one another).

"This process is fundamental for the formation of synapses, the connection point where cells communicate," says Twomey.

Implications for Movement Disorders and Mental Illness

The discovery could help accelerate the development of drugs for cerebellar ataxia, a disorder that affects movement and balance. Cerebellar ataxia can result from stroke, head injury, brain tumors, or certain neurodegenerative diseases, and it may also cause memory problems. In this condition, GluDs become "super-active" even when there is no electrical signaling in the brain. Twomey explains that a potential treatment approach would involve developing drugs that block this excessive activity.

In schizophrenia, the situation appears to be reversed. GluDs are less active than normal, and Twomey says future drugs could aim to boost their activity instead.

Potential Links to Aging and Memory Loss

The findings may also be relevant to aging and memory decline. Because GluDs help regulate synapses, drugs that target these proteins could help maintain synapse function over time. Synapses are essential for learning, memory, and the formation of thoughts.

"Because GluDs directly regulate synapses, we could potentially develop a targeted drug for any condition where synapses malfunction," Twomey says.

Next Steps and Ongoing Research

Looking ahead, Twomey says he plans to collaborate with pharmaceutical companies to further develop this therapeutic target. His team is also studying specific GluD mutations that have been directly linked to schizophrenia, anxiety, and other psychiatric disorders. The goal is to better understand how these conditions progress and to design more precise treatments.

Other Johns Hopkins scientists who contributed to the study include Haobo Wang, Fairine Ahmed, Jeffrey Khau, and Anish Kumar Mondal.

The Johns Hopkins University has filed a patent covering the techniques used to measure electrical currents from GluDs.

Funding for the research came from the National Institutes of Health (R35GM154904), the Searle Scholars Program, and the Diana Helis Henry Medical Research Foundation.