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Blockade of the KATP channel Kir6.2 by memantine represents a novel mechanism relevant to Alzheimer’s disease therapy

Molecular Psychiatry volume 23, pages 211–221 (2018)Cite this article

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Abstract

Here, we report a novel target of the drug memantine, ATP-sensitive K+ (KATP) channels, potentially relevant to memory improvement. We confirmed that memantine antagonizes memory impairment in Alzheimer’s model APP23 mice. Memantine increased CaMKII activity in the APP23 mouse hippocampus, and memantine-induced enhancement of hippocampal long-term potentiation (LTP) and CaMKII activity was totally abolished by treatment with pinacidil, a specific opener of KATP channels. Memantine also inhibited Kir6.1 and Kir6.2 KATP channels and elevated intracellular Ca2+ concentrations in neuro2A cells overexpressing Kir6.1 or Kir6.2. Kir6.2 was preferentially expressed at postsynaptic regions of hippocampal neurons, whereas Kir6.1 was predominant in dendrites and cell bodies of pyramidal neurons. Finally, we confirmed that Kir6.2 mutant mice exhibit severe memory deficits and impaired hippocampal LTP, impairments that cannot be rescued by memantine administration. Altogether, our studies show that memantine modulates Kir6.2 activity, and that the Kir6.2 channel is a novel target for therapeutics to improve memory impairment in Alzheimer disease patients.

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Acknowledgements

This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Health and Welfare of Japan (22390109 to KF; 20790398 to SM). Also, thanks to Professor Tsuyoshi Miyakawa for providing CaMKIIα +/− mice and Professor Susumu Seino for providing Kir6.1 +/− and Kir6.2 −/− mice. We also thank Novartis Pharma for providing APP23 mice.

Author Contributions

SM, NS, HT, YY, YS, and HS performed the experiments. TI and HY provided recombinant Kir6.1 or Kir6.2. H.S. provided knockout mice. JZY and TN provided critical reagents and advice. SM and KF wrote the manuscript and designed the study.

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Authors and Affiliations

  1. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan

    S Moriguchi, Y Yabuki, N Shioda, Y Sasaki, H Tagashira & K Fukunaga

  2. Department of Developmental Biology and Neuroscience, Graduate School of Life Sciences, Tohoku University, Sendai, Japan

    T Ishizuka & H Yawo

  3. Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    J Z Yeh & T Narahashi

  4. Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Japan

    H Sakagami

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  1. S Moriguchi
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Correspondence to S Moriguchi or K Fukunaga.

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Moriguchi, S., Ishizuka, T., Yabuki, Y. et al. Blockade of the KATP channel Kir6.2 by memantine represents a novel mechanism relevant to Alzheimer’s disease therapy. Mol Psychiatry 23, 211–221 (2018). https://doi.org/10.1038/mp.2016.187

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