| Summary: | 博士 === 國防醫學院 === 生命科學研究所 === 94 === We have previously demonstrated that the serum-and glucocorticoid-inducible kinase (SGK) plays a causal role in facilitating memory consolidation of spatial learning in rats, but the SGK signaling pathway’s role in formation of spatial memory is not known. The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) also plays an important and integrative role in synaptic plasticity and memory formation. In the present study, we examined whether SGK is a downstream target of the MAPK/ERK signaling cascade and whether ERK signaling to SGK mediates spatial memory formation in rats. By using in vitro kinase assay and immunoprecipitation kinase assay, we provide evidence that activated ERK directly phosphorylates SGK at serine 78 residue and ERK isolated from the hippocampus also phosphorylates SGK. Immunoprecipition and Western blot results showed that SGK is associated with ERK. Further, spatial training increased SGK phosphorylation at Thr256 and Ser422, but not at Ser78, whereas inhibition of ERK activity by PD98059 (an MEK inhibitor) significantly impaired spatial learning performance and decreased SGK phosphorylation at Ser78, Thr256 and Ser422 in the hippocampus. Prior administration of PD98059 also antagonized the enhancing effect of 12-O-tetradecanoylphorbol-13- acetate (TPA), a PKC activator that also causes ERK activation, on SGK and CREB phosphorylation. Moreover, TPA-induced SGK and CREB phosphorylation was abolished by prior SGKS78A mutant DNA transfection. On the other hand, SGKS78A mutant DNA transfection to the hippocampal CA1 area did not affect spatial memory formation, whereas SGKT256A mutant DNA transfection to CA1 area significantly impaired spatial memory formation.
ERK was known to regulate sgk mRNA expression. In the present study we have demonstrated that SGK is also a downstream target of the ERK signaling cascade; ERK directly phosphorylates SGK at Ser78 and indirectly activates SGK at Thr256 and Ser422 through unknown intermediate molecules. Further, ERK- mediated activation of SGK is involved in formation of spatial memory in rats.
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