Abdelrahman
Summary: Recent studies have provided new insights into the effects of ketamine on the brain, focusing on a specific subtype of NMDA receptors known as GluN1-2B-2D. Researchers utilized electron cryo-microscopy to observe how ketamine interacts with this receptor, uncovering various binding sites that play a crucial role in modulating brain activity.
These discoveries not only elucidate ketamine’s antidepressant properties but also underscore potential risks associated with its use. A deeper understanding of how this receptor functions could lead to the development of safer therapeutic alternatives with reduced side effects.
This investigation confirms the presence of the GluN1-2B-2D receptor in mammalian brains, settling a long-debated question in the scientific community. Ongoing research aims to enhance ketamine-based therapies to better address mental health issues.
Key Highlights:
- Discovery of Receptor: The study confirmed the identification of the GluN1-2B-2D NMDA receptor subtype targeted by ketamine.
- Binding Mechanism: Researchers employed electron cryo-microscopy to highlight various ways ketamine attaches to this receptor and obstructs its ion channel.
- Therapeutic Implications: Gaining insights into ketamine’s interaction with GluN1-2B-2D may inspire the creation of safer antidepressant options with fewer adverse effects.
Source: Cold Spring Harbor Laboratory (CSHL)
About Ketamine: Once recognized mainly for its recreational use and as a feline anesthetic—often referred to as “Special K”—ketamine has recently gained attention in the medical community. It is now prescribed to treat conditions ranging from depression to post-traumatic stress disorder (PTSD).
Dr. Hiro Furukawa from CSHL notes the ongoing debates surrounding ketamine’s use in vulnerable patients. The discussion intensified following the tragic death of actor Matthew Perry in 2024, which involved complications related to ketamine use for anxiety and depression.
“There are still numerous questions about ketamine’s impact on the brain,” Furukawa explains. It has long been suggested that the drug inhibits a specific type of NMDA receptor, known as GluN1-2B-2D. However, for some time, scientists questioned whether this receptor genuinely existed. A recent study from the Furukawa lab has now clarified this issue.
In their publication in the journal Neuron, Furukawa and postdoctoral researcher Hyunook Kang have successfully proven the presence of GluN1-2B-2D in mammalian brains. They’ve reconstructed a human variant of this receptor and utilized electron cryo-microscopy to observe its behavior in detail.
The scientists identified the mechanism that regulates GluN1-2B-2D movements, providing insight into how this receptor opens and closes its ion channel. Furthermore, they unveiled several binding modes through which ketamine interacts with GluN1-2B-2D.
Furukawa describes the findings, stating, “It’s like a mesh. In mere fractions of a second, ketamine can latch onto these sites, effectively shutting the channel.” While they identified four distinct binding patterns, researchers believe additional binding methods may exist.
Ketamine is thought to alleviate symptoms of depression and anxiety by influencing the movement of GluN1-2B-2D, but questions remain regarding how long the channel should stay open or closed, which likely varies by individual. Furthermore, the side effects of ketamine treatments can range from mild hallucinations to more severe psychological reactions. By understanding how GluN1-2B-2D operates, scientists hope to develop synthesized alternatives with fewer harmful effects.
These advancements present hope for millions struggling with depression and anxiety, as Furukawa and his team focus on refining therapeutic strategies utilizing this knowledge.
About this Research
Author: Samuel Diamond
Source: Cold Spring Harbor Laboratory
Contact: Samuel Diamond – CSHL
Image: Credited to Neuroscience News
Original Research: Open access article titled “Structural basis for channel gating and blockade in tri-heteromeric GluN1-2B-2D NMDA receptor” published in Neuron.
Abstract:
This study investigates the distinct activation processes of NMDA receptor (NMDAR) subtypes, emphasizing the tri-heteromeric GluN1-2B-2D variant known for its heightened sensitivity to ketamine, an antidepressant channel blocker. The research delineates its structural mechanisms during ligand gating and blockade, providing fresh insights into receptor dynamics that encompass therapeutic targeting for cognitive modifications.
