Zhao Yiwei, Zhu Lin, Yu Shaojun, Zhu Jing, Wang Chong
Department of Basic Medical Sciences of Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.
Neuroreport. 2016 Sep 28;27(14):1018-23. doi: 10.1097/WNR.0000000000000648.
The effects of Ca/calmodulin-dependent protein kinase II (CaMKII) on neuronal apoptosis are complex and contradictory, and the underlying mechanisms remain unclear. Bcl-2-interacting mediator of cell death (Bim) is an important proapoptotic protein under many physiological and pathophysiological conditions. However, there is no evidence that CaMKII and Bim are mechanistically linked in neuronal apoptosis. In this study, we showed that CaMKII inhibition by the inhibitors KN-62 and myristoylated autocamtide-2-related inhibitory peptide promoted apoptosis in cerebellar granule neurons in a dose-dependent manner. CaMKII inhibition increased Bim protein and messenger RNA levels. The expression of early growth response factor-1, a transcription factor of Bim, was also induced by CaMKII inhibitors. These data suggested that CaMKII repressed the transcriptional expression of Bim. Moreover, knockdown of Bim using small interfering RNAs attenuated the proapoptotic effects of CaMKII inhibition. Taken together, this is the first report to show that CaMKII inhibition transcriptionally upregulates Bim expression to promote neuronal apoptosis, providing new insights into the proapoptotic mechanism of CaMKII inhibition.
钙/钙调蛋白依赖性蛋白激酶II（CaMKII）对神经元凋亡的影响复杂且相互矛盾，其潜在机制仍不清楚。细胞死亡的Bcl-2相互作用介质（Bim）在许多生理和病理生理条件下是一种重要的促凋亡蛋白。然而，没有证据表明CaMKII和Bim在神经元凋亡中存在机制上的联系。在本研究中，我们发现抑制剂KN-62和肉豆蔻酰化自抑制肽-2相关抑制肽对CaMKII的抑制作用以剂量依赖方式促进小脑颗粒神经元凋亡。CaMKII抑制增加了Bim蛋白和信使RNA水平。早期生长反应因子-1（一种Bim的转录因子）的表达也被CaMKII抑制剂诱导。这些数据表明CaMKII抑制了Bim的转录表达。此外，使用小干扰RNA敲低Bim可减弱CaMKII抑制的促凋亡作用。综上所述，这是首次报道表明CaMKII抑制通过转录上调Bim表达来促进神经元凋亡，为CaMKII抑制的促凋亡机制提供了新见解。
