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Lack of hippocalcin causes impairment in Ras/extracellular signal‐regulated kinase cascade via a Raf‐mediated activation process

Hippocalcin (Hpca) is a member of the neuronal calcium sensor protein family and is highly expressed in hippocampal neurons. Hpca‐deficient (Hpca–/–) mice display a defect in cAMP response element‐binding protein (CREB) activation associated with impaired spatial and associative memory. Here we examine the involvement of Hpca in the extracellular signal‐regulated kinase (ERK) cascade leading to CREB activation, because application of PD98059, a broad ERK cascade inhibitor, has resulted in similar levels of CREB activation in Hpca–/– hippocampus. N‐methyl‐D‐aspartate (NMDA)‐ and KCl‐induced phosphorylation of ERK was significantly attenuated in Hpca–/– hippocampal slices, as was ionomycin‐induced phosphorylation of ERK, whereas forskolin and 12‐O‐tetradecanoyl‐phorbol‐13‐acetate (TPA) stimulation yielded indistinguishable levels of ERK phosphorylation in both wild‐type and Hpca–/– slices. In an in vitro reconstitution assay system, recombinant Hpca affected neither Raf‐1 protein kinase activity with recombinant MEK‐1 as a substrate nor MEK‐1 kinase activity with ERK2 as a substrate. Activation of Ras by NMDA and KCl stimulation of hippocampal slices showed no obvious changes between the two genotypes; however, phosphorylation of Raf‐1 was significantly lower in Hpca–/– slices. These results suggest that Hpca plays an important role in the activation of Raf conducted by Ras. © 2007 Wiley‐Liss, Inc.