The NMDAR protein plays a key role in various cognitive operations, especially memory. Its actions are highly synchronized, resembling a meticulously planned dance performance. Recently, researchers uncovered how this protein performs a challenging dance move akin to a ‘Twist’. This revelation could pave the way for the development of new drug compounds that interact with NMDAR more effectively.
Proteins are in a continuous state of motion, adjusting their structures to execute specific roles within our bodies. The NMDAR protein undertakes a particularly intricate dance in our brains, where even a minor misstep can result in various neurological issues. NMDAR interacts with the neurotransmitter glutamate and another molecule, glycine. These interactions dictate NMDAR’s movements. Once its routine concludes, the NMDAR opens up, creating an ion channel that produces electrical signals essential for cognitive tasks like memory.
The challenge has been that researchers couldn’t identify the final move in the NMDAR’s sequence—until now. Professor Hiro Furukawa from Cold Spring Harbor Laboratory and his team have decoded the vital motion where NMDAR shifts into an open state. Essentially, they have uncovered the NMDAR “Twist.”
To record this crucial step, Furukawa and his collaborators employed a method known as electron cryo-microscopy (cryo-EM), which freezes proteins to visualize them in real time. Initially, the team needed to stabilize a specific type of NMDAR, called GluN1-2B, in its open state for imaging. Furukawa joined forces with Professors Stephen Traynelis and Dennis Liotta from Emory University, and together they identified a molecule that helps keep NMDAR in its open configuration.
“It’s not the most stable form,” Furukawa notes. “Lots of components within NMDAR move independently, yet they must synchronize perfectly to open the ion channel. We require an exact amount of electrical signals at the right moments for appropriate behaviors and cognitive functions.”
The cryo-EM images enable scientists to observe exactly how the atoms of NMDAR move during its “Twist.” This insight could ultimately lead to drug compounds capable of restoring the correct movements in NMDARs that are underperforming. Enhanced medications targeting NMDARs might also be beneficial for treating neurological conditions such as Alzheimer’s and depression.
“Compounds tend to bind imperfectly to protein pockets at first. This can help us, along with chemists, to identify ways to fill those spaces more accurately. This could enhance the drug’s effectiveness. Additionally, the shape of the pocket is distinct, but other proteins might have similar shapes, which could cause side effects. Therefore, targeting specificity is crucial,” Furukawa elaborates.
There are indeed various types of NMDARs within the brain. Another recent research study from Furukawa’s lab has provided the first glimpse at the GluN1-3A NMDAR, which surprisingly exhibits entirely different movements. This distinct routine results in atypical electrical signal patterns.
In summary, we are mastering the Twist. Up next: the headspin.
