Sooraj Shah ’24

Neurological disorders affect 25 million people in the United States, which makes the study of NMDA receptors increasingly important. NMDA receptors are key contributors to regulation of memory and behavior in the human brain. NMDA (N-methyl-D-aspartate) receptor proteins are transmembrane proteins, and are in a subset of Ionotropic glutamate receptors (iGluRs), which contain 4 helices, the most significant of which is the M4 channel helix in which a glycine regulates ionic gate function. Random change of NMDA receptor gene structure results in de novo missense mutations, which inhibit the function of these glycine-regulated ion channels within the transmembrane. This in turn delays neurological development due to the resulting blockage of Ca²⁺, which act as messengers in the neurological structure of the brain. The focus of the study was to examine the effect of specific mutations on cell receptor gating, as prevention of the “de novo”  mutation can uncover possible new treatment for neurological disorders such as autism, epilepsy, and schizophrenia.

As with all proteins, NMDA receptors are characterized by the lifespan of their open state. An extraneous cell culture solution optimizing NMDA activity was applied to a set of mutated iGluRs units to find which were most affected by measuring their deactivation periods. Furthermore, the effect of the glycine chain substitution was tested on two specific iGluRs units, GluN2A and GluN2B.   This method revealed that the deactivation periods of the NMDA receptor were rapidly increasing, a sign that the mutation was causing a drastic effect on the glycine-regulated ionic channels. Upon further examination, the glycine was found to act as a door, allowing calcium ions to flow across the membrane. The mutation alters the structure of this glycine, leading to decreased neurological capability. In addition, the observed channel activity yielded little to no activity. This means the affected NMDA receptors were heavily contributing to the decreased neurological activity in the brain. The mutation also resulted in a glycine to alanine side chain substitution, which greatly minimizes the lifespan of the receptor. Since glycine offers the flexibility for the opening and closing of the channels, substitution of the glycine to alanine shortened the receptor’s longevity and shortened the length of the time the channels were open for. This shows that glycine was greatly responsible for pore regulation as part of the NMDA receptor. 

Understanding that missense mutations within the NMDA proteins in the brain heavily contribute to serious disorders is a key factor to finding a proper treatment. For example, since iGluRs units are expressed throughout adulthood, finding a way to stop the expression of the mutation or discovering a way to widen the period of functionality of ion channels is the next step to preventing these disorders. 

Works cited:

[1] L. Wollmuth et. al., A conserved glycine harboring disease-associated mutations permits NMDA receptor slow deactivation and high Ca²⁺ permeability. Nat. Commun 9, (2018) doi: https://doi.org/10.1038/s41467-018-06145-w

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