A 3D atomic model of a variation of the NMDA brain receptors, called the GluN1a-2C type. Targeting this type of receptor may help treat neuropsychiatric disorders like schizophrenia and Alzheimer’s. Credit: Furukawa Lab
N-methyl-D-aspartate (NMDA) receptors are responsible for mediating the passage of essential signals between neurons, and dysfunction in these receptors is believed to contribute to a wide range of neuropsychiatric conditions including depression, schizophrenia and Alzheimer’s disease. NMDA receptors are a key drug target for such disorders, and while some of these receptors’ structures have been widely studied, other variations found in different parts of the brain are less understood. Researchers at Cold Spring Harbor Laboratory (CSHL) have now used cryo-electron microscopy (cryo-EM) to reveal the 3D structures of four forms of NMDA receptors, expanding the possibilities for drug development for a number of brain disorders.
Single-particle cryo-EM is a technique that aids in determining the detailed 3D structures of biological molecules or complexes, such as protein complexes, with near-atomic resolution. Many high-resolution electron microscopy images obtained under specific cryogenic conditions are combined computationally in order to elucidate these structures. The researchers utilized this method to obtain the structures of four agonist-bound NMDA receptors containing various subunits: GluN1-2A-2C, GluN1-2D and two forms of GluN1-2C. GluN1-2C receptors were imaged both in the presence and absence of PYD-106, a positive allosteric potentiator, which enhances NMDA signaling.
The GluN1-2A-2C, GluN1-2D and GluN1-2C NMDA receptors are found in discrete regions of the brain, such as the cerebellum, at specific periods during brain development, and it is believed that low-functioning receptors containing GluN1-2C could be a cause of schizophrenia-like symptoms, explained corresponding author Hiro Furukawa. The researchers gained several insights into the assembly and function of the NMDA receptors from their images and 3D visualizations, such as the fact that PYD-106 binds to the GluN2C subunit in a “straight” conformation, while GluN1-2A-2C contains a GluN2C conformer that is insensitive to PYD-106, according to the paper. The information yielded from the study can serve as a blueprint for researchers to further study these receptors and potentially explore how to best target them for the treatment of neuropsychiatric disorders. This research was published in Molecular Cell.
“This NMDA receptor is such an important drug target. We hope our images, which visualize the receptor for the first time, will facilitate drug development across the field based on our structural information,” said first author Tsung-Han Chou.