Kitagawa Kazuo, Sasaki Tsutomu, Terasaki Yasukazu, Yagita Yoshiki, Mochizuki Hideki
Department of Neurology, Osaka University Graduate School of Medicine.
Rinsho Shinkeigaku. 2012;52(11):904-7. doi: 10.5692/clinicalneurol.52.904.
Ischemic tolerance is as powerful and reproducible for neuro-protection as hypothermia. Several pathways could be involved in acquisition of ischemic tolerance. CREB is an abundant transcription factor in the brain and plays critical role on synaptic plasticity and neuronal survival. CREB activation has been also shown to be involved in ischemic tolerance. Ischemia or oxygen-glucose deprivation leads to release of glutamate, which binds to synaptic NMDA receptor. Then, influx of calcium ions into intracellular space activates calcium-calmodulin dependent protein kinase (CaMK). CaMK I/IV phosphorylates Ser 133 of CREB, and Thr 484 of salt-inducible kinase (SIK). Phosphorylation of SIK2 at Thr 484 triggers degradation of SIK2 through ubiquitin proteasome system. SIK2 maintains the phosphorylation level of CREB-regulated transcriptional co-activator (CRTC). Degradation of SIK2 induces dephosphorylation of CRTC1, and moves CRTC1 from cytoplasm into nucleus. Thus CRTC1 binds to basic ZIP domain of CREB. Both Ser133 phosphorylation and CRTC1 bound to the basic ZIP domain of CREB enhances CRE-mediated transcription, induces gene expression of survival factors, and renders the neurons resistant to subsequent severe ischemia.
缺血耐受对神经保护的作用与低温一样强大且可重复。缺血耐受的获得可能涉及多种途径。CREB是大脑中一种丰富的转录因子，对突触可塑性和神经元存活起着关键作用。CREB的激活也被证明与缺血耐受有关。缺血或氧糖剥夺会导致谷氨酸释放，谷氨酸与突触NMDA受体结合。然后，钙离子流入细胞内空间激活钙调蛋白依赖性蛋白激酶（CaMK）。CaMK I/IV使CREB的Ser 133和盐诱导激酶（SIK）的Thr 484磷酸化。SIK2的Thr 484磷酸化通过泛素蛋白酶体系统触发SIK2的降解。SIK2维持CREB调节的转录共激活因子（CRTC）的磷酸化水平。SIK2的降解诱导CRTC1去磷酸化，并使CRTC1从细胞质转移到细胞核。因此，CRTC1与CREB的碱性ZIP结构域结合。CREB的Ser133磷酸化和与CREB碱性ZIP结构域结合的CRTC1都增强了CRE介导的转录，诱导存活因子的基因表达，并使神经元对随后的严重缺血具有抗性。
