Ketamine has gone from a club drug to a potential mental health treatment, but its safety remains hotly debated.
After Matthew Perry’s tragic overdose, researchers have intensified efforts to understand how the drug works. A new study finally proves the existence of a long-theorized NMDA receptor and shows precisely how ketamine binds to it, offering insights that could lead to safer antidepressant options.
Ketamine’s Hollywood Makeover
Ketamine’s reputation has evolved dramatically. Once known primarily as a party drug called “Special K” and used as an anesthetic for animals, it is now being prescribed by some doctors to treat mental health conditions such as post-traumatic stress disorder (Friends actor Matthew Perry, who overdosed on ketamine. His passing led to legal action, including charges against the doctor who had prescribed him ketamine for depression and anxiety.
Unraveling Ketamine’s Effect on the Brain
“Even putting this aside, many questions remain regarding how ketamine affects the brain,” says Furukawa. “It’s been suggested for over a decade that the drug blocks a specific kind of NMDA receptor (NMDAR), called GluN1-2B-2D.” There was one big problem with this theory. Scientists weren’t quite sure that GluN1-2B-2D existed. A new study from the Furukawa lab shines much-needed light on the situation.
Proving the Existence of a Mysterious Receptor
In a paper published today (February 14) in the journal Neuron, Furukawa and postdoc Hyunook Kang prove that GluN1-2B-2D does exist in the mammal brain. They then reconstruct a human version of GluN1-2B-2D. They don’t stop there. Using electron cryo-microscopy (cryo-EM), they capture GluN1-2B-2D in action. The neuroscientists identify the tension-and-release mechanism that controls GluN1-2B-2D movements. They can now see how this mysterious NMDAR opens and closes its ion channel pore. And they go another step further. They reveal several ways ketamine may bind to GluN1-2B-2D.
Capturing Ketamine in Action
A series of stunningly detailed visualizations show ketamine molecules becoming attached to specific parts of GluN1-2B-2D. “It’s like a mesh,” explains Furukawa. “Over tiny fractions of a second, ketamine can latch onto these sections and close off the channel.” Furukawa and his colleagues captured four binding patterns. However, they believe there are many other ways ketamine can take hold.
This 3D animation, from Cold Spring Harbor Laboratory Professor Hiro Furukawa and postdoc Hyunook Kang, illustrates the tension-and-release mechanism that controls how brain receptor GluN1-2B-2D opens and closes its ion channel pore. Credit: Furukawa lab/CSHL
The Future of Ketamine Therapy
It’s thought that ketamine may ease symptoms of depression and anxiety by affecting GluN1-2B-2D movement. But for how long should the channel remain open or closed? “This likely varies per patient,” Furukawa says. Likewise, side effects of ketamine therapy can range from mild hallucinations to full-on psychosis. However, if scientists can determine how GluN1-2B-2D movements affect the brain, they may be able to synthesize new versions of the drug with fewer harmful side effects. That could offer hope for millions of people living with depression and anxiety. So, that’s where Furukawa and his colleagues at CSHL will set their sights next.
Reference: “Structural basis for channel gating and blockade in tri-heteromeric GluN1-2B-2D NMDA receptor” by Hyunook Kang, Max Epstein, Tue G. Banke, Riley Perszyk, Noriko Simorowski, Srinu Paladugu, Dennis C. Liotta, Stephen F. Traynelis and Hiro Furukawa, 14 February 2025, Neuron.
DOI: 10.1016/j.neuron.2025.01.013
Cold Spring Harbor Laboratory
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