SIK2 is a key regulator for neuronal survival after ischemia via TORC1-CREB

Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Neuron (Impact Factor: 15.05). 01/2011; 69(1):106-19. DOI: 10.1016/j.neuron.2010.12.004
Source: PubMed


The cAMP responsive element-binding protein (CREB) functions in a broad array of biological and pathophysiological processes. We found that salt-inducible kinase 2 (SIK2) was abundantly expressed in neurons and suppressed CREB-mediated gene expression after oxygen-glucose deprivation (OGD). OGD induced the degradation of SIK2 protein concomitantly with the dephosphorylation of the CREB-specific coactivator transducer of regulated CREB activity 1 (TORC1), resulting in the activation of CREB and its downstream gene targets. Ca(2+)/calmodulin-dependent protein kinase I/IV are capable of phosphorylating SIK2 at Thr484, resulting in SIK2 degradation in cortical neurons. Neuronal survival after OGD was significantly increased in neurons isolated from sik2(-/-) mice, and ischemic neuronal injury was significantly reduced in the brains of sik2(-)(/-) mice subjected to transient focal ischemia. These findings suggest that SIK2 plays critical roles in neuronal survival, is modulated by CaMK I/IV, and regulates CREB via TORC1.

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    • "This hypothesis needs to be tested directly but is in keeping with human case reports of AD patients showing that cognitive decline is accompanied by slow decision-making and motor actions (Hebert et al. 2010; Buchman and Bennett 2011; Bennett et al. 2012). CRTC1 is implicated in dendrite arborization of developing cortical neurons (Li et al. 2009; Finsterwald et al. 2010), neuronal survival in response to ischemia (Sasaki et al. 2011), addiction mediated through brain reward circuits (Hollander et al. 2010; Dietrich et al. 2011), circadian clock entrainment (Jagannath et al. 2013; Sakamoto et al. 2013), mood regulation (Breuillaud et al. 2012), as well as hippocampal L-LTP and memory (Zhou et al. 2006; Kovacs et al. 2007; Sekeres et al. 2012). Our study provides new insight into how CRTC1-dependent gene expression is coincident with dysfunction on associative learning tasks at the early stages of Aβ pathology. "
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