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Effects of a ketamine metabolite on synaptic NMDAR function

Nature volume 546, pages E1–E3 (2017)Cite this article

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arising from P. Zanos et al. Nature 533, 481–486 (2016); doi:10.1038/nature17998

Clinical data have demonstrated rapid and sustained antidepressant effects of ketamine, a noncompetitive NMDAR (N-methyl-d-aspartate receptor) antagonist1. Recently, Zanos et al.2 claimed that the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) is essential for the antidepressant effects of ketamine in mice in an NMDAR-independent manner, although no alternative mechanism was proposed, beyond unspecific activation of AMPAR (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor)2. Here we report that (2R,6R)-HNK blocks synaptic NMDARs in a similar manner to its parent compound, and we show that the effects of (2R,6R)-HNK on intracellular signalling are coupled to NMDAR inhibition. These data demonstrate that (2R,6R)-HNK inhibits synaptic NMDARs and subsequently elicits the same signal transduction pathway previously associated with NMDAR inhibition by ketamine. There is a Reply to this Comment by Zanos, P. et al. Nature 546, http://dx.doi.org/10.1038/nature22085 (2017).

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Figure 1: (2R,6R)-HNK blocks NMDAR-mEPSCs and decreases eEF2 phosphorylation in hippocampal neurons.
Figure 2: (2R,6R)-HNK acts as open channel NMDAR blocker.

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Authors and Affiliations

  1. Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, 75390-9111, Texas, USA

    Kanzo Suzuki, Elena Nosyreva, Ege T. Kavalali & Lisa M. Monteggia

  2. Biopharmaceutical Product Development, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, 75390-9111, Texas, USA

    Kevin W. Hunt

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  1. Kanzo Suzuki
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  2. Elena Nosyreva
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  4. Ege T. Kavalali
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  5. Lisa M. Monteggia
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Correspondence to Lisa M. Monteggia.

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Suzuki, K., Nosyreva, E., Hunt, K. et al. Effects of a ketamine metabolite on synaptic NMDAR function. Nature 546, E1–E3 (2017). https://doi.org/10.1038/nature22084

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