Okadaic acid mediates tau phosphorylation via sustained activation of the L-voltage-sensitive calcium channel.
Accumulation of phosphorylated isoforms of the microtubule-associated protein tau is one hallmark of affected neurons in Alzheimer's disease (AD). This increase has been attributed to increased kinase or decreased phosphatase activity. Prior studies indicate that one of the kinases that phosphorylates tau (mitogen-activated protein kinase, or MAP kinase) does so at least in part indirectly within intact neuronal cells by phosphorylating and activating the L-voltage-sensitive calcium channel. Resultant calcium influx then fosters tau phosphorylation via one or more calcium-activated kinases. We demonstrate herein that treatment of differentiated SH-SY-5Y human neuroblastoma with the phosphatase inhibitor okadaic acid (OA) similarly may increase tau phosphorylation via sustained activation of the L-voltage-sensitive calcium channel. OA increased phospho-tau as indicated by increased immunoreactivity towards an antibody (PHF-1) directed against paired helical filaments from AD brain. This increase was blocked by co-treatment with the channel antagonist nimodipine. OA treatment increased channel phosphorylation. The increases in calcium influx, PHF-1 immunoreactivity and channel phosphorylation were all attenuated by co-treatment with PD98059, which inhibits MAP kinase activity, suggesting that OA mediates these effects at least in part via sustained activation of MAP kinase. These findings underscore that divergent and convergent kinase and phosphatase activities regulate tau phosphorylation.
Ekinci
Fatma J
FJ
Center for Cellular Neurobiology and Neurodegeneration Research, Department of Biological Sciences, University of Massachusetts Lowell, 1 University Avenue, Lowell, MA 01854, USA.
Ortiz
Daniela
D
Shea
Thomas B
TB
D000911:Antibodies, Monoclonal / Q000378:metabolism; D000941:Antigens / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D003720:Densitometry / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D042541:Intracellular Space / Q000378:metabolism; D009447:Neuroblastoma; D009553:Nimodipine / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects*; D021122:Protein Subunits / Q000378:metabolism; D056565:Sirtuin 2; D037761:Sirtuins; D014407:Tumor Cells, Cultured; D016875:tau Proteins / Q000378:metabolism*
C056167:Alzheimer's disease antigen; D000911:Antibodies, Monoclonal; D000941:Antigens; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009687:Nuclear Proteins; C085349:PHF-1 monoclonal antibody; D021122:Protein Subunits; C097475:Sirt2 protein, rat; D016875:tau Proteins; D019319:Okadaic Acid; D009553:Nimodipine; D056565:Sirtuin 2; D037761:Sirtuins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D002118:Calcium