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Inhibitory phosphorylation of GSK-3 by CaMKII couples depolarization to neuronal survival.

Authors: Song, B  Lai, B  Zheng, Z  Zhang, Y  Luo, J  Wang, C  Chen, Y  Woodgett, JR  Li, M 
Citation: Song B, etal., J Biol Chem. 2010 Dec 24;285(52):41122-34. doi: 10.1074/jbc.M110.130351. Epub 2010 Sep 14.
Pubmed: (View Article at PubMed) PMID:20841359
DOI: Full-text: DOI:10.1074/jbc.M110.130351

Glycogen synthase kinase-3 (GSK-3) plays a critical role in neuronal apoptosis. The two mammalian isoforms of the kinase, GSK-3alpha and GSK-3beta, are inhibited by phosphorylation at Ser-21 and Ser-9, respectively. Depolarization, which is vital for neuronal survival, causes both an increase in Ser-21/9 phosphorylation and an inhibition of GSK-3alpha/beta. However, the role of GSK-3 phosphorylation in depolarization-dependent neuron survival and the signaling pathway contributing to GSK-3 phosphorylation during depolarization remain largely unknown. Using several approaches, we showed that both isoforms of GSK-3 are important for mediating neuronal apoptosis. Nonphosphorylatable GSK-3alpha/beta mutants (S21A/S9A) promoted apoptosis, whereas a peptide encompassing Ser-9 of GSK-3beta protected neurons in a phosphorylation-dependent manner; these results indicate a critical role for Ser-21/9 phosphorylation on depolarization-dependent neuron survival. We found that Ser-21/9 phosphorylation of GSK-3 was mediated by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) but not by Akt/PKB, PKA, or p90(RSK). CaMKII associated with and phosphorylated GSK-3alpha/beta. Furthermore, the pro-survival effect of CaMKII was mediated by GSK-3 phosphorylation and inactivation. These findings identify a novel Ca(2+)/calmodulin/CaMKII/GSK-3 pathway that couples depolarization to neuronal survival.

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CRRD Object Information
CRRD ID: 10401822
Created: 2015-10-07
Species: All species
Last Modified: 2015-10-07
Status: ACTIVE



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