Hypoxic Preconditioning Maintains GLT-1 Against Transient Global Cerebral Ischemia Through Upregulating Cx43 and Inhibiting c-Src.
Hypoxic Preconditioning Maintains GLT-1 Against Transient Global Cerebral Ischemia Through Upregulating Cx43 and Inhibiting c-Src.
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低氧预处理通过上调 Cx43 和抑制 c-Src 维持 GLT-1 对抗短暂性全脑缺血。
DOI：
10.3389/fnmol.2018.00344
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发表时间：
2018
影响因子：
4.8
通讯作者：
Xu E
中科院分区：
文献类型：
--
作者：
Li K;Zhou H;Zhan L;Shi Z;Sun W;Liu D;Liu L;Liang D;Tan Y;Xu W;Xu E
短暂性脑缺血（tGCI）导致谷氨酸从神经元过度释放。星形胶质细胞谷氨酸转运蛋白-1 （GLT-1）和谷氨酰胺合成酶（GS）共同在维持正常的细胞外谷氨酸浓度中起主要作用。虽然我们之前的研究报道了通过缺氧预处理（HPC）减轻tgci诱导的成年大鼠海马角氨1 （CA1）神经元死亡，但其潜在机制尚未得到充分阐述。在本研究中，我们旨在探讨GLT-1和GS在HPC介导的抗tGCI神经保护中的作用，并确定这些作用是否可以通过连接蛋白43 （Cx43）和细胞src （c-Src）活性调节。我们发现HPC通过维持GLT-1表达和GS活性来降低tGCI后CA1细胞外谷氨酸水平。用二氢海碱盐（DHK）抑制GLT-1表达或用蛋氨酸亚砜胺（MSO）抑制GS活性可消除HPC诱导的神经保护作用。此外，在tGCI后，HPC显著上调Cx43并抑制CA1中p-c-Src的表达，而用Gap26抑制Cx43则显著逆转了这一作用。此外，4-氨基-5-（4-氯苯基）-7-（t-丁基）吡唑啉（3,4 -d）嘧啶（PP2）抑制p-c-Src可降低c-Src活性，增加GLT-1和Cx43蛋白水平，增强GS活性，从而降低tGCI后CA1细胞外谷氨酸水平。综上所述，我们的数据表明，HPC通过阻止GLT-1表达的降低和维持海马CA1中GS的活性，通过上调Cx43表达和抑制c-Src活性介导了细胞外谷氨酸的减少，从而抑制tGCI。
Transient global cerebral ischemia (tGCI) causes excessive release of glutamate from neurons. Astrocytic glutamate transporter-1 (GLT-1) and glutamine synthetase (GS) together play a predominant role in maintaining glutamate at normal extracellular concentrations. Though our previous studies reported the alleviation of tGCI-induced neuronal death by hypoxic preconditioning (HPC) in hippocampal Cornu Ammonis 1 (CA1) of adult rats, the underlying mechanism has not yet been fully elaborated. In this study, we aimed to investigate the roles of GLT-1 and GS in the neuroprotection mediated by HPC against tGCI and to ascertain whether these roles can be regulated by connexin 43 (Cx43) and cellular-Src (c-Src) activity. We found that HPC decreased the level of extracellular glutamate in CA1 after tGCI via maintenance of GLT-1 expression and GS activity. Inhibition of GLT-1 expression with dihydrokainate (DHK) or inhibition of GS activity with methionine sulfoximine (MSO) abolished the neuroprotection induced by HPC. Also, HPC markedly upregulated Cx43 and inhibited p-c-Src expression in CA1 after tGCI, whereas inhibition of Cx43 with Gap26 dramatically reversed this effect. Furthermore, inhibition of p-c-Src with 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo (3, 4-d) pyrimidine (PP2) decreased c-Src activity, increased protein levels of GLT-1 and Cx43, enhanced GS activity, and thus reduced extracellular glutamate level in CA1 after tGCI. Collectively, our data demonstrated that reduced extracellular glutamate induced by HPC against tGCI through preventing the reduction of GLT-1 expression and maintaining GS activity in hippocampal CA1, which was mediated by upregulating Cx43 expression and inhibiting c-Src activity.
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