Quality control of NMDA receptors: the influence of the ligand-binding domain

NMDA receptors play a key role in signal transmission between neurons and are essential for memory formation at the cellular level. They help strengthen the connections between neurons, which is one of the basic mechanisms of memory formation and learning. At the same time, it has been shown that their dysfunction is associated with a number of neurological and neuropsychiatric disorders, such as epilepsy, schizophrenia, Alzheimer’s disease and depression, among others.

In a study published in the prestigious Journal of Neuroscience (IF 4,4) (open in a new window), published by the Society for Neuroscience, one of the leading organisations in the field, a research team from the Department of Neurochemistry analysed more than 80 mutant variants of NMDA receptors. They also focused on the pathogenic mutations identified in patients with disorders in the ligand-binding domain. This publication is particularly significant because it is the first-authored article by our PhD student, Jakub Netolický.

The ligand-binding domain (LBD) is part of a protein (receptor) that can recognise and bind a small signalling molecule (ligand) in the NMDA receptor. This domain is essential, as the receptor only opens when two molecules bind to it simultaneously – glutamate, the primary excitatory neurotransmitter in the brain, and glycine. Each of these molecules binds to its own LBD. The opening of the receptor is associated with the influx of ions that transmit information to the neuron.

Using electrophysiological methods, fluorescence microscopy and molecular modelling, scientists have described the mechanisms that cells use to control the correct composition of receptors before they are transported to the membrane, focusing on changes in the LBD.

The results showed that:

• Each subunit of the NMDA receptor (GluN1 and GluN2A) is “controlled” separately,
• Cells recognise even very subtle differences in receptor structure,
• Some mutations prevent the receptor from getting to the surface,
• A relationship between the number of receptors on the surface and their sensitivity to glycine and glutamate was observed only in the GluN1 subunit.

Studies investigating the quality control of NMDA receptors provide new insights into how mutations affect these receptors’ correct composition and function, which play a key role in a number of serious neurological diseases. These findings help to better understand the molecular causes of these diseases, paving the way for the development of targeted drugs and more accurate diagnostics.