Regulation of CaMKII by alpha4/PP2Ac contributes to learning and memory.
Ca(2+)-dependent CaMKIIalpha activation with autophosphorylation plays an essential role in learning and memory. The regulation of CaMKIIalpha by dephosphorylation by protein phosphatase 1 (PP1) has been demonstrated. We addressed whether the protein phosphatase 2A (PP2A) that is abundant in the brain could be involved in the regulation of CaMKIIalpha. CaMKIIalpha was associated with the catalytic subunit of PP2A (PP2Ac) and alpha4, a regulator of PP2A. To investigate whether alpha4 plays an important role in the CNS, we established a neuron specific Cre transgenic mouse and a neuron specific alpha4 deficient mouse (N-alpha4 KO mouse). This N-alpha4 KO mouse showed impaired learning and memory in a water maze and also shuttle-box avoidance test. The activity of CaMKIIalpha also increased in hippocampus. An overexpression of alpha4 in the neuronal cell line demonstrated the activity of CaMKIIalpha to be regulated by alpha4. alpha4 and PP2Ac were localized in the cytoplasm but not in the postsynaptic density (PSD), thus suggesting that the dephosphorylation of CaMKIIalpha by alpha4/PP2Ac occurred in the cytoplasm. These results suggest that alpha4 and PP2A may thus play an important role in CaMKIIalpha regulation and thereby also influence learning.
Yamashita
Takeshi
T
Department of Immunology, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto 860-8556, Japan.
Inui
Seiji
S
Maeda
Kazuhiko
K
Hua
Ding Rong
DR
Takagi
Katsumasa
K
Fukunaga
Kohji
K
Sakaguchi
Nobuo
N
D048868:Adaptor Proteins, Signal Transducing; D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D047468:Immunoprecipitation / Q000379:methods; D036341:Intercellular Signaling Peptides and Proteins; D007858:Learning / Q000502:physiology*; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones; D009447:Neuroblastoma; D010749:Phosphoprotein Phosphatases / Q000172:deficiency / Q000378:metabolism*; D010750:Phosphoproteins / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D011930:Reaction Time / Q000502:physiology; D014162:Transfection / Q000379:methods
D048868:Adaptor Proteins, Signal Transducing; C092377:Igbp1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D010750:Phosphoproteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2