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首页> 外文期刊>Journal of pharmacological sciences. >Functional proteins involved in regulation of intracellular ca(2+) for drug development: role of calcium/calmodulin-dependent protein kinases in ischemic neuronal death.
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Functional proteins involved in regulation of intracellular ca(2+) for drug development: role of calcium/calmodulin-dependent protein kinases in ischemic neuronal death.

机译:参与细胞内ca(2+)药物开发调控的功能蛋白:钙/钙调蛋白依赖性蛋白激酶在缺血性神经元死亡中的作用。

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摘要

Excessive elevation of intracellular calcium level seems to be a trigger of ischemic neuronal injury. Calcium/calmodulin (CaM)-dependent protein kinase kinase (CaM-KK) is an upstream kinase for CaM kinase IV (CaM-KIV) that was reported to prevent apoptosis through phosphorylation of CREB (cyclic AMP responsive element-binding protein). We here observed that CaM-KK could directly activate Akt, thereby preventing apoptosis in cultured cells. Then we examined changes in Akt and CaM-KIV activities in gerbil forebrain ischemia. In 5-min-ischemia-caused delayed neuronal death in hippocampal CA1 neurons, Akt and CaM-KIV activities were decreased after reperfusion. On the other hand, during induction of ischemic tolerance, Akt activity gradually and persistently increased in the CA1 neurons with transient increase in CREB phosphorylation. Inhibition of Akt activity with wortmannin or CREB-DNA binding with CRE-decoy injection resulted in failure of generation of ischemic tolerance. These results indicated activation of Akt and CaM-KIV play important roles in induction of the ischemic tolerance. Activation of CaM-KK may provide a new strategy for overcoming the ischemic stress.
机译:细胞内钙水平的过度升高似乎是缺血性神经元损伤的诱因。钙/钙调蛋白(CaM)依赖性蛋白激酶激酶(CaM-KK)是CaM激酶IV(CaM-KIV)的上游激酶,据报道可通过CREB(环AMP响应元件结合蛋白)的磷酸化来防止细胞凋亡。我们在这里观察到CaM-KK可以直接激活Akt,从而防止培养细胞的凋亡。然后,我们检查了沙鼠前脑缺血后Akt和CaM-KIV活性的变化。在5分钟局部缺血引起的海马CA1神经元神经元死亡中,再灌注后Akt和CaM-KIV活性降低。另一方面,在诱导缺血耐受期间,CA1神经元中的Akt活性逐渐且持续增加,而CREB磷酸化的瞬时增加。用渥曼青霉素抑制Akt活性或用CRE诱饵注射结合CREB-DNA导致缺血耐受的产生失败。这些结果表明Akt和CaM-KIV的激活在诱导缺血耐受中起重要作用。 CaM-KK的激活可能提供克服缺血应激的新策略。

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