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Complex functional phenotypes of NMDA receptor disease variants
Gary J Iacobucci1, Beiying Liu2, Han Wen3
1Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA. garyiaco@buffalo.edu.
Molecular Psychiatry
|September 18, 2022
Summary
Altered NMDA receptor interactions due to genetic variants disrupt normal brain function. Both increased and decreased interaction strength at key sites cause severe receptor dysfunction, impacting neuropsychiatric health.
Area of Science:
- Neuroscience
- Molecular Biology
- Biophysics
Background:
- NMDA receptors are crucial for central nervous system excitatory synapses.
- Dysfunction of NMDA receptors is linked to severe neuropsychiatric disorders.
- Genetic variants in NMDA receptors are found in patients, but their functional impact is poorly understood.
Purpose of the Study:
- To investigate the pathogenic mechanisms of two GluN2A variants in NMDA receptors.
- To elucidate the role of specific GluN2A subunit residues (P552 and F652) and their pathogenic substitutions (P552R, F652V) in receptor function.
Main Methods:
- Utilized molecular dynamics simulations to model receptor behavior.
- Employed single-molecule electrophysiology to analyze receptor function.
- Examined the impact of specific residue substitutions on interaction energy and receptor gating.
Main Results:
- A dynamic interaction between P552 and F652 stabilizes NMDA receptors in open conformations.
- Shortened side chains (P552A, F652V) disrupted this interaction, leading to severe deficits in gating, conductance, and permeability.
- The P552R substitution resulted in stronger interaction, causing distinct but abnormal electrical responses.
Conclusions:
- The dynamic contact between P552 and F652 is essential for NMDA receptor activation.
- Both diminished and enhanced interactions at this site lead to receptor dysfunction.
- Subtle structural changes in NMDA receptors can cause complex alterations, challenging simple therapeutic classifications.
