Wang Shuchao, Liao Lvshuang, Huang Yanxia, Wang Mi, Zhou Hongkang, Chen Dan, Liu Fengxia, Ji Dan, Xia Xiaobo, Jiang Bing, Huang Jufang, Xiong Kun
Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China.
Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States.
Front Cell Neurosci. 2019 Jun 25;13:276. doi: 10.3389/fncel.2019.00276. eCollection 2019.
In our previous study, we reported that peptidyl-prolyl isomerase 1 (Pin1)-modulated regulated necrosis (RN) occurred in cultured retinal neurons after glutamate injury. In the current study, we investigated the role of calcium/calmodulin-dependent protein kinase II (CaMKII) in Pin1-modulated RN in cultured rat retinal neurons, and in an animal model. We first demonstrated that glutamate might lead to calcium overloading mainly through ionotropic glutamate receptors activation. Furthermore, CaMKII activation induced by overloaded calcium leads to Pin1 activation and subsequent RN. Inactivation of CaMKII by KN-93 (KN, i.e., a specific CaMKII inhibitor) application can decrease the glutamate-induced retinal neuronal RN. Finally, by using an animal model, we also demonstrated the important role of CaMKII in glutamate-induced RN in rat retina. In addition, flash electroretinogram results provided evidence that the impaired visual function induced by glutamate can recover after CaMKII inhibition. In conclusion, CaMKII is an up-regulator of Pin1 and responsible for the RN induced by glutamate. This study provides further understanding of the regulatory pathway of RN and is a complementary mechanism for Pin1 activation mediated necrosis. This finding will provide a potential target to protect neurons from necrosis in neurodegenerative diseases, such as glaucoma, diabetic retinopathy, and even central nervous system diseases.
在我们之前的研究中，我们报道了在谷氨酸损伤后，肽基脯氨酰异构酶1（Pin1）调节的程序性坏死（RN）在培养的视网膜神经元中发生。在当前研究中，我们研究了钙/钙调蛋白依赖性蛋白激酶II（CaMKII）在培养的大鼠视网膜神经元以及动物模型中Pin1调节的RN中的作用。我们首先证明谷氨酸可能主要通过离子型谷氨酸受体激活导致钙超载。此外，钙超载诱导的CaMKII激活导致Pin1激活及随后的RN。应用KN-93（KN，即一种特异性CaMKII抑制剂）使CaMKII失活可减少谷氨酸诱导的视网膜神经元RN。最后，通过使用动物模型，我们还证明了CaMKII在谷氨酸诱导的大鼠视网膜RN中的重要作用。此外，闪光视网膜电图结果提供了证据，表明谷氨酸诱导的视觉功能损害在CaMKII抑制后可以恢复。总之，CaMKII是Pin1的上调因子，并负责谷氨酸诱导的RN。本研究进一步阐明了RN的调节途径，是Pin1激活介导的坏死的补充机制。这一发现将为保护神经元免受神经退行性疾病（如青光眼、糖尿病性视网膜病变，甚至中枢神经系统疾病）中的坏死提供一个潜在靶点。
