黑料吃瓜资源

Ketamine has received a Hollywood makeover. It used to be known as a rave drug (street name special K) and cat anesthetic. However, in recent years, some doctors have prescribed ketamine to treat conditions from post-traumatic stress disorder to depression. 鈥淭丑别 practice is not without controversy,鈥� notes 黑料吃瓜资源 (CSHL) Professor Hiro Furukawa.

鈥楽hould we give a hallucinogen to patients in compromised mental states?鈥� wonder ketamine鈥檚 skeptics. The controversy came to a head in 2024 following the death of Matthew Perry. The popular TV actor, best known as Chandler on NBC鈥檚 Friends, died from a ketamine overdose. One person charged in connection with Perry鈥檚 death was the doctor who鈥檇 prescribed him ketamine for depression and anxiety.

This 3D animation illustrates the tension-and-release mechanism that controls how brain receptor GluN1-2B-2D opens and closes its ion channel pore.

鈥淓ven putting this aside, many questions remain regarding how ketamine affects the brain,鈥� says Furukawa. 鈥淚t鈥檚 been suggested for over a decade that the drug blocks a specific kind of NMDA receptor (NMDAR), called GluN1-2B-2D.鈥� There was one big problem with this theory. Scientists weren鈥檛 quite sure that GluN1-2B-2D existed. A new study from the Furukawa lab shines much-needed light on the situation.

In a paper published 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鈥檛 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.

A series of stunningly detailed visualizations show ketamine molecules becoming attached to specific parts of GluN1-2B-2D. 鈥淚t鈥檚 like a mesh,鈥� explains Furukawa. 鈥淥ver tiny fractions of a second, ketamine can latch onto these sections and close off the channel.鈥� Furukawa and his colleagues captured four binding patterns. However, they believe there are many other ways ketamine can take hold.

It鈥檚 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? 鈥淭his likely varies per patient,鈥� 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鈥檚 where Furukawa and his colleagues at CSHL will set their sights next.

Written by: Samuel Diamond, Senior Communications Strategist | [email protected] | 516-367-5055

Funding

National Institutes of Health, Austin鈥檚 Purpose, Robertson Research Fund, Doug Fox Alzheimer鈥檚 Fund, Heartfelt Wings Foundation, Gertrude and Louis Feil Family Trust, National Research Foundation of Korea

Citation

Kang, H., et al., 鈥淪tructural basis for channel gating and blockade in tri-heteromeric GluN1-2B-2D NMDA receptor鈥�, Neuron, February 14, 2025. DOI:

Core Facilites

鈥淭丑别 Electron Cryomicroscopy (Cryo-EM) Facility offers researchers access to cutting-edge technology that has made it possible to visualize complex biological systems at near atomic resolution and detail, providing novel molecular insight into human biology and disease.鈥� 鈥� Cryo-EM Facility Manager Dennis Thomas