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Complex functional phenotypes of NMDA receptor disease variants

Molecular Psychiatry volume 27, pages 5113–5123 (2022)Cite this article

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Abstract

NMDA receptors have essential roles in the physiology of central excitatory synapses and their dysfunction causes severe neuropsychiatric symptoms. Recently, a series of genetic variants have been identified in patients, however, functional information about these variants is sparse and their role in pathogenesis insufficiently known. Here we investigate the mechanism by which two GluN2A variants may be pathogenic. We use molecular dynamics simulation and single-molecule electrophysiology to examine the contribution of GluN2A subunit-residues, P552 and F652, and their pathogenic substitutions, P552R and F652V, affect receptor functions. We found that P552 and F652 interact during the receptors’ normal activity cycle; the interaction stabilizes receptors in open conformations and is required for a normal electrical response. Engineering shorter side-chains at these positions (P552A and/or F652V) caused a loss of interaction energy and produced receptors with severe gating, conductance, and permeability deficits. In contrast, the P552R side chain resulted in stronger interaction and produced a distinct, yet still drastically abnormal electrical response. These results identify the dynamic contact between P552 and F652 as a critical step in the NMDA receptor activation, and show that both increased and reduced communication through this interaction cause dysfunction. Results show that subtle differences in NMDA receptor primary structure can generate complex phenotypic alterations whose binary classification is too simplistic to serve as a therapeutic guide.

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Fig. 1: Two residues important for normal neurological function interact during NMDA receptor gating.
Fig. 2: NMDA receptor variants associated with neurological dysfunction display a broad range of gating perturbations.
Fig. 3: NMDA receptor variants associated with neurological dysfunction display changes in conductance and permeability.
Fig. 4: Disease-associated variants display complex functional changes.
Fig. 5: Proposed role of P552/F652 interaction in the gating reaction of NMDA receptors.

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Acknowledgements

We thank Jamie Abbott, PhD for helpful critiques and technical support in cell culture and molecular biology. This study was funded by NIH R01NS108750 and R01NS097016 to GKP.

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  1. These authors contributed equally: Gary J. Iacobucci, Beiying Liu.

  2. These authors jointly supervised this work: Wenjun Zheng, Gabriela K. Popescu.

Authors and Affiliations

  1. Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA

    Gary J. Iacobucci, Beiying Liu, Brittany Sincox & Gabriela K. Popescu

  2. Department of Physics, College of Arts and Sciences, State University of New York at Buffalo, Buffalo, NY, USA

    Han Wen & Wenjun Zheng

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Contributions

GJI and GKP conceived the study. HW and WZ performed and analyzed MD simulations. GJI, BL, and BS performed and analyzed electrophysiology experiments. GJI, BL, and GKP prepared figures and wrote the paper.

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Correspondence to Gary J. Iacobucci, Wenjun Zheng or Gabriela K. Popescu.

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Iacobucci, G.J., Liu, B., Wen, H. et al. Complex functional phenotypes of NMDA receptor disease variants. Mol Psychiatry 27, 5113–5123 (2022). https://doi.org/10.1038/s41380-022-01774-6

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