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Updated: Nov 23, 2025
04:48
A High-throughput Calcium-flux Assay to Study NMDA-receptors with Sensitivity to Glycine/D-serine and Glutamate
Published on: July 10, 2018
9.6K
Cross-subunit interactions that stabilize open states mediate gating in NMDA receptors
Gary J Iacobucci1, Han Wen2, Matthew Helou1
1Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, SUNY, Buffalo, NY 14203.
Summary
A novel interaction stabilizes NMDA receptors after opening, crucial for synaptic function. This finding clarifies late-stage activation and impacts understanding of pathogenic variants affecting charge transfer.
Area of Science:
- Neuroscience
- Molecular biology
- Biophysics
Background:
- N-methyl-D-aspartate (NMDA) receptors are critical ion channels in central nervous system synapses.
- Receptor activation involves complex, kinetically distinct steps with incompletely understood structural underpinnings.
Purpose of the Study:
- To elucidate the structural basis of late-stage NMDA receptor activation.
- To identify specific molecular interactions stabilizing the open state of the receptor.
Main Methods:
- Molecular and kinetic simulations were employed.
- Double-mutant cycle analyses were performed to probe protein-protein interactions.
Main Results:
- A direct chemical interaction between GluN1-I642 and GluN2A-L550 was identified, stabilizing the open state of NMDA receptors.
- This interaction occurs late in the activation process and influences current decay.
- Absence of this interaction, as seen in the pathogenic GluN1-I642L variant, impairs charge transfer.
Conclusions:
- The GluN1-I642/GluN2A-L550 interaction is a key structural element in late NMDA receptor activation.
- Understanding this interaction is vital for comprehending NMDA receptor function and dysfunction in disease.
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