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Allosteric inhibition of NMDA receptors by low dose ketamine

Molecular Psychiatry (2024)Cite this article

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Abstract

Ketamine, a general anesthetic, has rapid and sustained antidepressant effects when administered at lower doses. Anesthetic levels of ketamine reduce excitatory transmission by binding deep into the pore of NMDA receptors where it blocks current influx. In contrast, the molecular targets responsible for antidepressant levels of ketamine remain controversial. We used electrophysiology, structure-based mutagenesis, and molecular and kinetic modeling to investigate the effects of ketamine on NMDA receptors across an extended range of concentrations. We report functional and structural evidence that, at nanomolar concentrations, ketamine interacts with membrane-accessible hydrophobic sites on NMDA receptors, which are distinct from the established pore-blocking site. These interactions stabilize receptors in pre-open states and produce an incomplete, voltage- and pH-dependent reduction in receptor gating. Notably, this allosteric inhibitory mechanism spares brief synaptic-like receptor activations and preferentially reduces currents from receptors activated tonically by ambient levels of neurotransmitters. We propose that the hydrophobic sites we describe here account for clinical effects of ketamine not shared by other NMDA receptor open-channel blockers such as memantine and represent promising targets for developing safe and effective neuroactive therapeutics.

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Fig. 1: Extended dose-response relationships.
Fig. 2: Putative interactions between S-KET+ and NMDA receptors.
Fig. 3: Probing the predicted interactions between KET and NMDA receptors.
Fig. 4: Predicted contacts and effects of KET enantiomers.
Fig. 5: Probing membrane-access and mechanism of receptor inhibition by low dose KET.

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Data availability

Structures and trajectories were deposited in Zenodo https://zenodo.org/records/10711149. Requests for further information, resources, or reagents should be directed to and will be fulfilled by the corresponding author (GKP).

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Acknowledgements

We thank James Hitt for initiating this project, and Lynn Ziegler for technical assistance.

Funding

GKP (R35NS132248, R01MH118298, and R01NS108750) and JAA (5T32GM099607).

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Author notes

  1. These authors contributed equally: Jamie A. Abbott, Han Wen.

Authors and Affiliations

  1. Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, 14203, USA

    Jamie A. Abbott, Beiying Liu, Sheila S. Gupta, Gary J. Iacobucci & Gabriela K. Popescu

  2. Department of Physics, College of Biological Sciences, Buffalo, NY, 14260, USA

    Han Wen & Wenjun Zheng

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Contributions

JAA (whole-cell electrophysiology data collection and analyses, model validation, editing). HW (molecular simulations investigation, analyses, and visualization, and editing). BL (whole-cell and single-channel data collection and analyses). SVG (single-channel data collection and curation). GJI (single-channel and whole-cell data analysis, kinetic modeling and simulations, model validation, visualization, and editing). WZ (conceptualization, supervision, and editing). GKP (conceptualization, supervision, data analyses, integration, and writing).

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Correspondence to Gabriela K. Popescu.

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Abbott, J.A., Wen, H., Liu, B. et al. Allosteric inhibition of NMDA receptors by low dose ketamine. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02729-9

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