Johns Hopkins Discovers Brain Proteins Previously Thought Dormant Are Active Drug Targets

The Discovery That Changed Everything

The proteins in question are delta type ionotropic glutamate receptors, known as GluDs. Despite being linked to psychiatric disorders including anxiety and schizophrenia for years, scientists struggled to understand how these proteins actually function, making therapeutic development extremely difficult.

Edward Twomey, assistant professor of biophysics and biophysical chemistry at Johns Hopkins University School of Medicine, led the research team that made this breakthrough. Using cryo-electron microscopy, they demonstrated that GluDs contain an ion channel at their centre that facilitates interactions with neurotransmitters, the chemical messengers that enable brain cells to communicate at synapses.

This discovery fundamentally changes our understanding of these proteins. For decades, they were assumed to be dormant structures in the brain with no active function. The new research proves they are very much active and playing a vital role in neural communication.

How It Works

To understand the significance of this discovery, it helps to understand how neurons communicate. Brain cells connect at junction points called synapses, where they exchange information using chemical messengers called neurotransmitters. The GluD proteins sit at these synapses and regulate how signals are transmitted between neurons.

The research showed that GluD receptors function as ligand gated ion channels, meaning they open and close in response to specific chemical signals, allowing ions to flow through and modulate neuronal activity. This mechanism is crucial for maintaining proper brain function, particularly in regions involved in learning, memory, motor coordination, and emotional regulation.

Treatment Implications for Multiple Conditions

The discovery opens treatment avenues for several neurological and psychiatric conditions, each requiring a different therapeutic approach based on whether GluD activity is too high or too low.

In cerebellar ataxia, a disorder affecting movement and balance that can result from stroke, head injury, or neurodegenerative diseases, GluD proteins become super active even without normal electrical signalling in the brain. A treatment approach could involve developing drugs that block this excessive activity, essentially turning down the volume on these overactive proteins.

In schizophrenia, the opposite problem occurs. GluD proteins are underactive, leading to disrupted neural communication. Future medications could aim to boost their functionality instead, effectively turning up the volume to restore normal signalling.

The findings may also apply to ageing and memory decline. Because GluD proteins help regulate synapses essential for learning and memory, targeted drugs could help maintain synapse function over time, potentially slowing cognitive decline in older adults.

Twomey emphasised the broad potential of this discovery, noting that because GluD receptors directly regulate synapses, researchers could potentially develop a targeted drug for any condition where synapses malfunction. This includes not only schizophrenia and movement disorders but also autism spectrum disorder and various forms of anxiety.

Moving Towards Clinical Applications

Twomey and his team are now working to translate these findings into actual treatments. He plans to collaborate with pharmaceutical companies to advance this therapeutic target from basic research to drug development.

His team is also investigating specific GluD mutations linked to schizophrenia and anxiety to better understand disease progression and design more precise treatments. By understanding exactly how different mutations affect GluD function, researchers can develop drugs tailored to specific genetic variations of these conditions.

Johns Hopkins University has filed a patent covering the techniques used to measure electrical currents from GluD proteins, protecting the intellectual property behind this breakthrough methodology.

A New Direction for Psychiatric Medicine

This research represents a significant shift in how scientists approach psychiatric and neurological disorders. Rather than focusing solely on well understood neurotransmitter systems like dopamine and serotonin, this discovery opens up an entirely new target for drug development.

The ability to modulate GluD activity up or down depending on the specific condition offers a more nuanced approach to treatment. Instead of one size fits all medications, future therapies could be precisely calibrated to address the specific dysfunction in each disorder.

The research also highlights the importance of questioning long held scientific assumptions. For decades, the scientific community accepted that GluD proteins were non functional, yet this turned out to be completely wrong. The discovery serves as a reminder that even well established scientific consensus can be overturned with new evidence and better technology.

As pharmaceutical companies begin working with this new target, patients with currently difficult to treat conditions may have new hope for more effective therapies in the coming years.