Pin1 Is Regulated by CaMKII Activation in Glutamate-Induced Retinal Neuronal Regulated Necrosis
Pin1 Is Regulated by CaMKII Activation in Glutamate-Induced Retinal Neuronal Regulated Necrosis
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Pin1 在谷氨酸诱导的视网膜神经元调节性坏死中受 CaMKII 激活的调节
DOI：
10.3389/fncel.2019.00276
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发表时间：
2019
影响因子：
5.3
通讯作者：
Xiong Kun
中科院分区：
文献类型：
--
作者：
Wang Shuchao;Liao Lvshuang;Huang Yanxia;Wang Mi;Zhou Hongkang;Chen Dan;Liu Fengxia;Ji Dan;Xia Xiaobo;Jiang Bing;Huang Jufang;Xiong Kun
在我们以前的研究中，我们报道了肽基脯氨酰异构酶1（Pin 1）调节的调节性坏死（RN）发生在培养的视网膜神经元谷氨酸损伤后。在目前的研究中，我们研究了钙/钙调素依赖性蛋白激酶II（CaMK II）在培养的大鼠视网膜神经元Pin 1调制RN中的作用，并在动物体内模型中。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Pin 1激活和随后的RN。KN-93（KN，即，特异性CaMKII抑制剂）应用可以降低谷氨酸诱导的视网膜神经元RN。最后，通过使用动物体内模型，我们还证明了CaMK II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证据表明，谷氨酸诱导的视觉功能受损可以在CaMKII抑制后恢复。总之，CaMKII是Pin 1的上调因子，并负责谷氨酸诱导的RN。这项研究提供了RN的调节途径的进一步理解，是Pin 1激活介导的坏死的补充机制。这一发现将提供一个潜在的目标，以保护神经元坏死的神经退行性疾病，如青光眼，糖尿病视网膜病变，甚至中枢神经系统疾病。
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 in vivo 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 in vivo 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.