Differential contribution of individual receptor subunits of N-methyl-d-aspartate to ischemic neuronal damage.

cAMP反应元件结合蛋白（CREB）在广泛的生物学和病理生理过程中发挥作用。我们发现，盐诱导激酶2（SIK 2）在神经元中大量表达，并抑制CREB介导的基因表达后，氧-葡萄糖剥夺（OGD）。OGD诱导SIK 2蛋白的降解，同时伴有CREB特异性调节CREB活性的辅激活因子转导子1（TORC 1）的去磷酸化，导致CREB及其下游基因靶点的激活。Ca（2+）/钙调素依赖性蛋白激酶I/ IV能够在Thr 484磷酸化SIK 2，导致SIK 2在皮质神经元中降解。从sik 2（-/-）小鼠分离的神经元中，OGD后的神经元存活率显著增加，并且在经受短暂局灶性缺血的sik 2（-/-）小鼠的脑中，缺血性神经元损伤显著减少。这些发现表明，SIK 2在神经元存活中起着关键作用，由CaMK I/ IV调节，并通过TORC 1调节CREB。

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.