Calcineurin inhibition prevents calpain-mediated proteolysis of tau in differentiated PC12 cells.
The effects of calcium influx on tau levels and phosphorylation were examined in differentiated PC12 cells. Maitotoxin-induced calcium influx resulted in time- and concentration-dependent tau dephosphorylation and degradation. Incubation of PC12 cells with a membrane-permeable calpain inhibitor blocked maitotoxin-induced tau degradation, suggesting the involvement of calpain in calcium-stimulated tau turnover. Okadaic acid or the calcineurin inhibitor FK520 partially inhibited maitotoxin-induced tau dephosphorylation at the Tau-1 epitope, indicating both phosphatase 2A/1 and calcineurin were involved. In addition, FK520, but not okadaic acid, blocked the maitotoxin-induced tau degradation, demonstrating that dephosphorylation of specific tau epitopes by was essential for calpain-mediated tau degradation. Moreover, maitotoxin effects were likely independent of tau association with microtubules because maitotoxin induced tau degradation and dephosphorylation in the presence of either nocodazole or taxol. These data provide evidence that calpain is involved in tau turnover in situ and calcineurin plays an important role in modulating tau susceptibility to calpain.
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, 35294-0017, USA.
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D000818:Animals; D015153:Blotting, Western; D019703:Calcineurin / Q000494:pharmacology*; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002454:Cell Differentiation; D002462:Cell Membrane / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000939:Epitopes / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D008387:Marine Toxins / Q000494:pharmacology; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D035964:Oxocins; D016716:PC12 Cells; D010447:Peptide Hydrolases / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D054648:Protein Phosphatase 2; D051381:Rats; D016875:tau Proteins / Q000378:metabolism*; D000095702:Polyether Toxins
D019703:Calcineurin; D002154:Calpain; D004791:Enzyme Inhibitors; D000939:Epitopes; D008387:Marine Toxins; D035964:Oxocins; D010447:Peptide Hydrolases; D011480:Protease Inhibitors; D054648:Protein Phosphatase 2; D016875:tau Proteins; C020394:maitotoxin; D000095702:Polyether Toxins