Moriguchi, Shigeki, Ishizuka, Toru, Yabuki, Yasushi, Shioda, Norifumi, Sasaki, Yuzuru, Takashira, Hideaki, Yeh, Jay Z, Narahashi, Toshio, Sakagami, Hiroyuki and Fukunaga, Kohji (2016) The KATP channel Kir6.2 is new target for Alzheimer’s disease therapy. Molecular Psychiatry, 00 (00). pp. 1-11. ISSN 1359-41841476-5578

Abstract

Here we report a novel target, ATP-sensitive K+ (KATP) channels, of memantine
implicated in memory improvement. We confirmed that memantine improves memory
impairment in Alzheimer’s model APP23 mice. Unexpectedly, memantine increased CaMKII
activity in APP23 hippocampus, and memantine-induced enhancement of hippocampal LTP
and CaMKII activity was totally abolished by treatment with pinacidil, a specific opener of
KATP channels. We therefore confirmed that memantine inhibits KATP channels Kir6.1 and
Kir6.2 and elevates intracellular Ca2+ concentrations in neuro2A cells engineered to
overexpress Kir6.1 or Kir6.2. Kir6.2 was preferentially expressed in postsynaptic regions,
whereas Kir6.1 was predominant in hippocampal neuron dendrites. Finally, we confirmed that
Kir6.2 heterozygous mutant mice exhibit severe memory deficits and hippocampal LTP
impairment that cannot be rescued by memantine administration. Taken together, our studies
show that memantine modulates activity of Kir6.2, suggesting that the channel is a novel target
for therapeutics to improve memory impairment in AD patients.

Item Type:	Article
Date Deposited:	12 Nov 2016 00:45
Last Modified:	12 Nov 2016 00:45
URI:	https://oak.novartis.com/id/eprint/26437