In this issue of Neuron, Sasaki et al. (2011) shed light on the issue by identifying ischemia-induced degradation of salt-inducible kinase 2 (SIK2) as a pivotal step in the activation of CREB-dependent transcription, an effect involving dephosphorylation

and nuclear import of the CREB coactivator transducer of regulated CREB activity 1 (TORC1) ( Figure 1). The findings establish SIK2 and TORC1 as critical regulators of a novel endogenous neuroprotective pathway with significant implications for the treatment of cerebrovascular pathologies and other brain diseases linked to NMDARs. CREB activation involves multiple signaling cascades that phosphorylate AG-014699 datasheet CREB to assemble a functional transcriptional complex (Lonze and Ginty, 2002). Therefore, as they set out to investigate post-ischemic CREB-dependent transcription, Sasaki et al. first examined CREB phosphorylation

at the well-described regulatory Ser133 using oxygen glucose deprivation (OGD) in cortical neuronal cultures, a model that recapitulates key features of ischemia-reperfusion injury. They uncovered an intriguing temporal dissociation between CREB phosphorylation and the upregulation of CRE activity, as measured using gene reporter assays, suggestive of a phosphorylation-independent mechanism of CREB activation. Consequently, they hypothesized the involvement of a recently discovered family of CREB transcriptional coactivators the TORC family of proteins (Conkright et al., 2003 and Iourgenko et al., 2003). TORCs translocate from the cytoplasm to the Dipeptidyl peptidase nucleus in Antidiabetic Compound Library response to increases in calcium and cAMP, a step that requires dephosphorylation (Bittinger et al., 2004 and Screaton et al., 2004). Once in the nucleus, TORCs bind CREB and promote CREB-dependent gene expression, an effect independent of Ser133 phosphorylation (Bittinger et al., 2004 and Conkright et al., 2003). Sasaki et al. (2011) found that, after OGD, TORC1 is dephosphorylated and translocated to the nucleus with a temporal profile that fits well with the upregulation of CRE activity. Using constitutively active or dominant-negative constructs,

they provided convincing evidence that TORC1 upregulation or downregulation is causally linked to CREB-dependent gene expression and neuronal survival after OGD. Although TORC1 has already been implicated in other CREB-dependent neuronal functions, such as synaptic plasticity (Kovacs et al., 2007 and Zhou et al., 2006), the findings of Sasaki et al. (2011) establish for the first time the involvement of TORC1-CREB in an intrinsic cell survival program triggered by hypoxia-ischemia. While dephosphorylation is necessary for its nuclear translocation, phosphorylation can sequester TORC in the cytoplasm (Screaton et al., 2004). To begin to unravel the factors regulating TORC phosphorylation during OGD, Sasaki et al. (2011) focused on AMPK, SIK1, and SIK2, kinases known to phosphorylate TORC.