Blockade of the K ATP channel Kir6.2 by memantine represents a novel mechanism relevant to Alzheimer's disease therapy

S. Moriguchi*, T. Ishizuka, Y. Yabuki, N. Shioda, Y. Sasaki, H. Tagashira, H. Yawo, J. Z. Yeh, H. Sakagami, T. Narahashi, K. Fukunaga

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Here, we report a novel target of the drug memantine, ATP-sensitive K + (K ATP ) 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 K ATP channels. Memantine also inhibited Kir6.1 and Kir6.2 K ATP channels and elevated intracellular Ca 2+ 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.

Original languageEnglish (US)
Pages (from-to)211-221
Number of pages11
JournalMolecular Psychiatry
Volume23
Issue number2
DOIs
StatePublished - Feb 1 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Fingerprint

Dive into the research topics of 'Blockade of the K ATP channel Kir6.2 by memantine represents a novel mechanism relevant to Alzheimer's disease therapy'. Together they form a unique fingerprint.

Cite this