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Cleavage of GSK ‐3β by calpain counteracts the inhibitory effect of Ser9 phosphorylation on GSK ‐3β activity induced by H 2 O 2
Author(s) -
Feng Ye,
Xia Yiyuan,
Yu Guang,
Shu Xiji,
Ge Haoliang,
Zeng Kuan,
Wang Jianzhi,
Wang Xiaochuan
Publication year - 2013
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12285
Subject(s) - calpain , phosphorylation , gsk 3 , gsk3b , hek 293 cells , chemistry , oxidative stress , kinase , cyclin dependent kinase 5 , microbiology and biotechnology , biochemistry , protein kinase a , biology , mitogen activated protein kinase kinase , enzyme , gene
Glycogen synthase kinase‐3 beta (GSK‐3β) dysfunction may play an essential role in the pathogenesis of psychiatric, metabolic, neurodegenerative diseases, in which oxidative stress exists concurrently. Some studies have shown that GSK‐3β activity is up‐regulated under oxidative stress. This study evaluated how oxidative stress regulates GSK‐3β activity in human embryonic kidney 293 (HEK293)/Tau cells treated with hydrogen peroxide (H 2 O 2 ). Here, we show that H 2 O 2 induced an obvious increase of GSK‐3β activity. Surprisingly, H 2 O 2 dramatically increased phosphorylation of GSK‐3β at Ser9, an inactive form of GSK‐3β,while there were no changes of phosphorylation of GSK‐3β at Tyr216. Moreover, H 2 O 2 led to a transient [Ca 2+ ] i elevation, and simultaneously increased the truncation of GSK‐3β into two fragments of 40 kDa and 30 kDa, whereas inhibition of calpain decreased the truncation and recovered the activity of GSK‐3β. Furthermore, tau was hyperphosphorylated at Ser396, Ser404, and Thr231, three most common GSK‐3β targeted sites after 100 μM H 2 O 2 administration in HEK293/Tau cells, whereas inhibition of calpain blocked the tau phosphorylation. In addition, we found that there were no obvious changes of Cyclin‐dependent kinase 5 (CDK5) expression (responsible for tau phosphorylation) and of p35 cleavage, the regulatory subunit of CDK5 in H 2 O 2 ‐treated HEK293/Tau cells. In conclusion, Ca 2+ ‐dependent calpain activation leads to GSK‐3β truncation, which counteracts the inhibitory effect of Ser9 phosphorylation, up‐regulates GSK‐3β activity, and phosphorylates tau in H 2 O 2 ‐treated HEK293/Tau cells.