Summary: New research sheds light on how ketamine affects the brain by targeting a specific NMDA receptor subtype, Glun1-2B-2D. Scientists used electron cryomicroscopy to capture how ketamine binds to this receptor, revealing multiple attachment sites that affect brain activity.
These findings help explain the effects of ketamine antidepressants, but also highlight the risks associated with their use. Understanding how this receptor opens and closes can pave the way for safer alternatives with fewer side effects.
This study confirms the presence of Glun1-2B-2D in the mammalian brain and resolves years of scientific debate. Future research aims to improve ketamine-based treatments and improve mental health therapies.
Important facts
Receptor Discovery: Scientists have confirmed the presence of Glun1-2B-2D, a key NMDA receptor subtype targeted by ketamine. Binding mechanism: Electrofreezing system salience caused ketamine to attach and block the ion channels of this receptor. Glun1-2B-2D can lead to safer antidepressants with fewer side effects.
Source: CSHL
Ketamine has undergone a Hollywood transformation. It was once known as a Rave Drug (street name Special K) and a cat anesthetic.
However, in recent years, some doctors have prescribed ketamine to treat conditions ranging from post-traumatic stress disorder to depression.
“This practice is not without controversy,” says Professor Hirofurukawa, professor at Cold Spring Harbor Institute (CSHL).
“Should we give hallucinogens to patients with compromised mental states?” I wondered about ketamine skeptics. The controversy came to mind in 2024 after the death of Matthew Perry.
The popular TV actor, best known as Chandler, NBC friend, died of an overdose of ketamine. One person indicted in connection with Perry’s death was a doctor who prescribed ketamine due to depression and anxiety.
“Even if I put this aside, there are still many questions about how ketamine affects the brain,” says Furukawa.
“For over a decade, it has been suggested that drugs block certain types of NMDA receptors (NMDARs), called Glun1-2B-2D,” one major problem with this theory. Scientists were not convinced that Glun1-2B-2D would exist. The new research from Furukawa Lab sheds much needed light on the situation.
A paper published in Neuron, Furukawa and Postdoc Hyunook Kang demonstrates that Glun1-2B-2D is present in the mammalian brain. Next, we will reconstruct the human version of Glun1-2B-2D. They don’t stop there. Using Electron Cryo-Microscopy (Cryo-EM), they capture the working Glun1-2B-2D.
Neuroscientists identify the mechanisms of tension and release that control the movement of Glun1-2B-2D. They can now see how this mysterious Nmdar opens and closes the pores of the ion channel. And they’re going a step further. They reveal several ways in which ketamine binds to Glun1-2B-2D.
A series of surprisingly detailed visualizations show that ketamine molecules are attached to specific portions of Glun1-2B-2D.
“It’s like mesh,” explains Furukawa. “In a small fraction of 1 second, ketamine can latch into these sections to close the channel.”
Furukawa and his colleagues captured four conjugation patterns. However, they believe there are many other ways ketamine can be established.
Ketamine is thought to be able to alleviate symptoms of depression and anxiety by affecting Glun1-2B-2D movement. But how long should the channel be left open and closed?
“This is likely to vary from patient to patient,” says Furukawa.
Similarly, the side effects of ketamine therapy can range from mild hallucinations to total psychosis. However, if scientists can determine how Glun1-2B-2D movements affect the brain, they could potentially be able to synthesize newer versions of the drug with fewer harmful side effects.
It can bring hope to millions of people with depression and anxiety. So, it’s where Furukawa and his colleagues at CSHL next set their sights.
About this psychopharmacology and neuroscience research news
Author: Samuel Diamond
Source: CSHL
Contact: Samuel Diamond – CSHL
Image: Image credited to Neuroscience News
Original research: Open access.
Hiro Furukawa et al. Neurons
Abstract
Structural basis of channel gating and sequestration in triheteromolic Glun1-2B-2D NMDA receptors
Discrete activation of N-methyl-D-aspartate receptor (NMDAR) subtypes by glutamic acid and co-angular glycine is fundamental to neuroplasticity.
The triheteromolic receptor, a distinct variant, containing glycine-bound Glun1 and two glutamate-bound Glun2 subunits, is a unique pharmacology that significantly enhances sensitivity to the antidepressant channel blocker S-(+)-ketamine. indicates the characteristics.
Despite its importance, the structural mechanisms underlying ligand gating and channel blockade in triheteromolic NMDARs remain poorly understood.
Here we identify triheteromolic Glun1-2B-2D NmDARs in adult brains, characterize, activate, inhibit, and resolve structures of S-(+)-ketamine blocked states.
These structures regulate tension between the extracellular domain and transmembrane channels, revealing the ligand-dependent conformational dynamics governing channel gating and sequestration.
Furthermore, we show that inhibitor-DQP-997-74 selectively separates linker tension in Glun2D and provides insight into subtype-selective targeting of cognitive modulation.
