Summary: New research reveals how tiny electrical gates in the brain, known as NMDA receptors, control learning, memory, and neuron survival. Using cryo-electron microscopy, scientists captured atomic-level images showing how a natural neurosteroid, 24S-HC, holds these channels wide open, while a synthetic compound locks them partially shut.
The team found that fully open channels allow calcium and sodium to flood into neurons, whereas partially open channels restrict calcium—preventing potential damage. This discovery could lead to therapies that precisely modulate brain signaling to protect against Alzheimer’s disease, stroke, and other neurodegenerative disorders.
Key Facts
- Molecular Gatekeepers: NMDA receptors regulate electrical signaling by controlling the flow of calcium and sodium ions in neurons.
- Precision Control: Natural and synthetic regulators can fine-tune these ion gates, balancing learning-related calcium flow without triggering neuron damage.
- Therapeutic Potential: Targeting NMDARs could lead to safer treatments for neurodegeneration, memory loss, and stroke recovery.
Source: CSHL
As information zings from cell to cell inside the brain, bursts of electricity spur its transmission.
At Cold Spring Harbor Laboratory (CSHL), scientists have turned their attention to the tiny pores that let charged ions enter a cell—and the molecular gatekeepers that help control them.
CSHL structural biologist Hiro Furukawa studies NMDA receptors (NMDARs). These ion channels open in response to chemical signals from neurons or drugs. The channels must be carefully regulated. When they open too wide or stay shut for too long, it can interfere with learning and memory. This can lead to neurodegenerative conditions like Alzheimer’s disease.
Now, Professor Furukawa and postdoc Hyunook Kang have captured detailed images of an NMDAR held wide open by one of the brain’s natural gatekeepers, a neurosteroid called 24S-HC. They’ve also seen how a synthetic regulator latches onto the NMDAR to prevent it from fully opening.
Their images, produced with a powerful method called cryo-electron microscopy, show four rod-like parts of the NMDAR bend out of the way to fully open the channel. They also reveal how the regulator locks two of those rods in position, keeping the channel from opening all the way.
Understanding how natural and synthetic regulators interact with NMDARs will inform the design of safe and effective therapies to treat disease. Imagine a chemical doorstop for the brain’s electrical gates.
Furukawa’s group teamed up with researchers at Emory University to measure how much electricity flows through an NMDAR in its different states. Unsurprisingly, a fully open channel lets more ions through than a partially open one. In the brain, greater ion flow increases neural signaling.
Additionally, while a wide-open channel lets both sodium and calcium into a neuron, a partially open channel is more selective. Sodium gets through easily. However, it’s harder for calcium to pass. That has important implications for therapy,
Furukawa explains: “You need calcium for learning and memory, but when there’s too much, it degenerates neurons. You also need sodium to generate electrical signals. If you can control how much calcium goes in without affecting sodium going in, you’ll maintain close to normal electrical activity. This could be an effective strategy for neurodegeneration as well as strokes.”
The researchers point out that our brains contain many kinds of NMDARs and neurosteroids. It’s up to neuroscientists like Furukawa and Kang to figure out how those crucial molecules interact.
The solutions may provide important tools for fine-tuning signaling in the brain, opening the door for new and improved therapies as well as better mental health outcomes.
Key Questions Answered:
A: They visualized how the receptors open and close in response to natural and synthetic molecules, revealing precise structural changes that control ion flow.
A: Calcium is vital for learning and memory, but too much can kill neurons—so balancing its entry is key to preventing brain degeneration.
A: By designing molecules that act like adjustable “doorstops,” researchers could fine-tune brain signaling to support cognition and protect against damage.
About this neuroscience research news
Author: Samuel Diamond
Source: CSHL
Contact: Samuel Diamond – CSHL
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Mechanism of conductance control and neurosteroid binding in NMDA receptors” by Hiro Furukawa et al. Nature
Abstract
Mechanism of conductance control and neurosteroid binding in NMDA receptors
Ion-channel activity reflects a combination of open probability and unitary conductance. Many channels display subconductance states that modulate signalling strength, yet the structural mechanisms governing conductance levels remain incompletely understood.
Here we report that conductance levels are controlled by the bending patterns of pore-forming transmembrane helices in the heterotetrameric neuronal channel GluN1a-2B N-methyl-D-aspartate receptor (NMDAR).
Our single-particle electron cryomicroscopy (cryo-EM) analyses demonstrate that an endogenous neurosteroid and synthetic positive allosteric modulator (PAM), 24S-hydroxycholesterol (24S-HC), binds to a juxtamembrane pocket in the GluN2B subunit and stabilizes the fully open-gate conformation, where GluN1a M3 and GluN2B M3′ pore-forming helices are bent to dilate the channel pore.
By contrast, EU1622-240 binds to the same GluN2B juxtamembrane pocket and a distinct juxtamembrane pocket in GluN1a to stabilize a sub-open state whereby only the GluN2B M3′ helix is bent.
Consistent with the varying extents of gate opening, the single-channel recordings predominantly show full-conductance and subconductance states in the presence of 24S-HC and EU1622-240, respectively.
Another class of neurosteroid, pregnenolone sulfate, engages a similar GluN2B pocket, but two molecules bind simultaneously, revealing a diverse neurosteroid recognition pattern.
Our study identifies that the juxtamembrane pockets are critical structural hubs for modulating conductance levels in NMDAR.