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

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.

journal_name

Mol Psychiatry

journal_title

Molecular psychiatry

authors

Moriguchi S,Ishizuka T,Yabuki Y,Shioda N,Sasaki Y,Tagashira H,Yawo H,Yeh JZ,Sakagami H,Narahashi T,Fukunaga K

doi

10.1038/mp.2016.187

subject

Has Abstract

pub_date

2018-02-01 00:00:00

pages

211-221

issue

2

eissn

1359-4184

issn

1476-5578

pii

mp2016187

journal_volume

23

pub_type

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