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.

• Authors: S Moriguchi, T Ishizuka, Y Yabuki, N Shioda, Y Sasaki, H Tagashira, H Yawo, J Z Yeh, H Sakagami, T Narahashi, K Fukunaga
• Journal: Molecular psychiatry (Mol Psychiatry) Vol. 23 Issue 2 Pg. 211-221 (02 2018) ISSN: 1476-5578 [Electronic] England
• PMID: 27777420 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Kir6.2 channel
• Potassium Channels
• Potassium Channels, Inwardly Rectifying
• mitochondrial K(ATP) channel
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Memantine

Topics

• Alzheimer Disease (metabolism)
• Animals
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (drug effects)
• Dendrites
• Disease Models, Animal
• Hippocampus (drug effects)
• Humans
• Long-Term Potentiation (drug effects)
• Memantine (metabolism, pharmacology)
• Memory (drug effects, physiology)
• Memory Disorders (drug therapy)
• Mice
• Mice, Transgenic
• Neurons
• Phosphorylation
• Potassium Channels (drug effects)
• Potassium Channels, Inwardly Rectifying (drug effects)
• Pyramidal Cells
• Synapses
• Temporal Lobe