title: Blockade of the KATPchannel 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 KATPchannels. Memantine also inhibited Kir6.1 and Kir6.2 KATPchannels 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: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors: S
authors: S
authors: Moriguchi
authors: Department of Developmental Biology and Neuroscience, Graduate School of Life Sciences, Tohoku University, Sendai, Japan.
authors: T
authors: T
authors: Ishizuka
authors: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors: Y
authors: Y
authors: Yabuki
authors: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors: N
authors: N
authors: Shioda
authors: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors: Y
authors: Y
authors: Sasaki
authors: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors: H
authors: H
authors: Tagashira
authors: Department of Developmental Biology and Neuroscience, Graduate School of Life Sciences, Tohoku University, Sendai, Japan.
authors: H
authors: H
authors: Yawo
authors: Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors: J Z
authors: JZ
authors: Yeh
authors: Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Japan.
authors: H
authors: H
authors: Sakagami
authors: Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors: T
authors: T
authors: Narahashi
authors: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors: K
authors: K
authors: Fukunaga
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000187:drug effects; D003712:Dendrites; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects; D006801:Humans; D017774:Long-Term Potentiation / Q000187:drug effects; D008559:Memantine / Q000378:metabolism / Q000494:pharmacology*; D008568:Memory / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons; D010766:Phosphorylation; D015221:Potassium Channels / Q000187:drug effects; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects*; D017966:Pyramidal Cells; D013569:Synapses; D013702:Temporal Lobe; D000099161:Kcnj11 Channel
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D008559:Memantine; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel; C117780:mitochondrial K(ATP) channel