Inhibition of PP-2A upregulates CaMKII in rat forebrain and induces hyperphosphorylation of tau at Ser 262/356

Autor: Inge Grundke-Iqbal, Malika Bennecib, Khalid Iqbal, Cheng-Xin Gong
Rok vydání: 2001
Předmět:
Threonine
Time Factors
environment and public health
Biochemistry
Calcium calmodulin protein kinase II
Structural Biology
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
Phosphoprotein Phosphatases
Serine
Enzyme Inhibitors
Phosphorylation
Oxazoles
biology
Chemistry
Autophosphorylation
Up-Regulation
Female
Alzheimer disease
medicine.medical_specialty
Protein phosphatase-2A
Metabolically active brain slice
Blotting
Western
Phosphatase
Tau protein
Biophysics
Hyperphosphorylation
tau Proteins
Dephosphorylation
Prosencephalon
Ca2+/calmodulin-dependent protein kinase
Internal medicine
Okadaic Acid
Genetics
medicine
Animals
Rats
Wistar
Protein kinase A
Molecular Biology
Ionophores
Protein phosphatase-1
Protein phosphatase 1
Cell Biology
Rats
enzymes and coenzymes (carbohydrates)
Endocrinology
Calcium-Calmodulin-Dependent Protein Kinases
biology.protein
Marine Toxins
Abnormally hyperphosphorylated tau
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Zdroj: FEBS Letters. 490:15-22
ISSN: 0014-5793
DOI: 10.1016/s0014-5793(01)02127-5
Popis: The regulation of the activity of CaMKII by PP-1 and PP-2A, as well as the role of this protein kinase in the phosphorylation of tau protein in forebrain were investigated. The treatment of metabolically active rat brain slices with 1.0 microM okadaic acid (OA) inhibited approximately 65% of PP-2A and had no significant effect on PP-1 in the 16000xg tissue extract. Calyculin A (CL-A), 0.1 microM under the same conditions, inhibited approximately 50% of PP-1 and approximately 20% of PP-2A activities. In contrast, a mixture of OA and CL-A practically completely inhibited both PP-2A and PP-1 activities. The inhibition of the two phosphatase activities or PP-2A alone resulted in an approximately 2-fold increase in CaMKII activity and an approximately 8-fold increase in the phosphorylation of tau at Ser 262/356 in 60 min. Treatment of the brain slices with KN-62, an inhibitor of the autophosphorylation of CaMKII at Thr 286/287, produced approximately 60% inhibition in CaMKII activity and no significant effect on tau phosphorylation at Ser 262/356. The KN-62-treated brain slices when further treated with OA and CL-A did not show any change in CaMKII activity. In vitro, both PP-2A and PP-1 dephosphorylated tau at Ser 262/356 that was phosphorylated with purified CaMKII. These studies suggest (i) that in mammalian forebrain the cytosolic CaMKII activity is regulated mainly by PP-2A, (ii) that CaMKII is the major tau Ser 262/356 kinase in brain, and (iii) that a decrease in PP-2A/PP-1 activities in the brain leads to hyperphosphorylation of tau not only by inhibition of its dephosphorylation but also by promoting the CaMKII activity.
Databáze: OpenAIRE
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