Yoon Hana, Oh Young Taek, Lee Jung Yeon, Choi Ji Hyun, Lee Ju Hie, Baik Hyung Hwan, Kim Sung Soo, Choe Wonchae, Yoon Kyung-Sik, Ha Joohun, Kang Insug
Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
Biochem Biophys Res Commun. 2008 Jul 4;371(3):495-500. doi: 10.1016/j.bbrc.2008.04.102. Epub 2008 Apr 28.
AMP-activated protein kinase (AMPK) is a key regulator of energy homeostasis. Kainic acid (KA), a prototype excitotoxin is known to induce brain-derived neurotrophic factor (BDNF) in brain. In this study, we examined the role of AMPK in KA-induced BDNF expression in C6 glioma cells. We showed that KA and KA receptor agonist induced activation of AMPK and KA-induced AMPK activation was blocked by inhibition of Ca(2+)/calmodulin-dependent protein kinase kinase (CaMKK) beta. We then showed that inhibition of AMPK by compound C, a selective inhibitor of AMPK, or small interfering RNA of AMPKalpha1 blocked KA-induced BDNF mRNA and protein expression. Inhibition of AMPK blocked KA-induced phosphorylation of CaMKII and I kappaB kinase (IKK) in C6 cells. Finally, we showed that inhibition of AMPK reduced DNA binding and transcriptional activation of nuclear factor-kappaB (NF-kappaB) in KA-treated cells. These results suggest that AMPK mediates KA-induced BDNF expression by regulating NF-kappaB activation.
AMP激活的蛋白激酶（AMPK）是能量稳态的关键调节因子。海藻酸（KA）作为一种兴奋性毒素原型，已知可在脑中诱导脑源性神经营养因子（BDNF）。在本研究中，我们检测了AMPK在KA诱导的C6胶质瘤细胞BDNF表达中的作用。我们发现KA和KA受体激动剂可诱导AMPK激活，且抑制钙/钙调蛋白依赖性蛋白激酶激酶（CaMKK）β可阻断KA诱导的AMPK激活。随后我们发现，用AMPK选择性抑制剂Compound C或AMPKα1小干扰RNA抑制AMPK，可阻断KA诱导的BDNF mRNA和蛋白表达。抑制AMPK可阻断KA诱导的C6细胞中CaMKII和IκB激酶（IKK）的磷酸化。最后，我们发现抑制AMPK可降低KA处理细胞中核因子κB（NF-κB）的DNA结合及转录激活。这些结果表明，AMPK通过调节NF-κB激活介导KA诱导的BDNF表达。
