Target of HIV-1 Envelope Glycoprotein gp120-Induced Hippocampal Neuron Damage: Role of Voltage-Gated K(+) Channel Kv2.1.
Target of HIV-1 Envelope Glycoprotein gp120-Induced Hippocampal Neuron Damage: Role of Voltage-Gated K(+) Channel Kv2.1.
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HIV-1 包膜糖蛋白 gp120 诱导的海马神经元损伤的靶标：电压门控 K( ) 通道 Kv2.1 的作用。
DOI：
10.1089/vim.2015.0020
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发表时间：
2015-11
期刊：
影响因子：
--
通讯作者：
Xiao H.
中科院分区：
文献类型：
--
作者：
Zhu J;Gao R;Wang J;Xiao H.
人类免疫缺陷病毒1型（HIV-1）包膜糖蛋白120（gp 120）对海马神经元具有毒性，并参与HIV-1相关性神经认知障碍（HAND）的发病机制。越来越多的证据表明，电压门控性钾通道，尤其是外向延迟整流钾通道（Ik）在gp 120诱导的皮层神经元死亡中起着重要作用。然而，gp 120介导的神经毒性导致海马神经元损伤的潜在机制仍然知之甚少。本研究采用全细胞膜片钳技术记录培养的海马神经元，发现gp 120可显著增加外向延迟整流钾电流（Ik）。Western blot结果显示，gp 120能显著上调Kv2.1蛋白表达，这与细胞内Ik浓度的增加相一致。通过Western blot和末端脱氧核苷酸转移酶dUTP缺口末端标记分析，发现gp 120诱导的神经元损伤主要是由于Kv2.1通道的激活和caspase-3激活介导的细胞凋亡，因为Kv2.1通道的药物阻断在很大程度上减弱了gp 120诱导的细胞损伤和caspase-3表达。此外，p38 MAPK被证明参与gp 120诱导的海马神经损伤，因为p38 MAPK拮抗剂（SB 203580）部分取消gp 120诱导的Kv2.1上调和神经细胞凋亡。综上所述，这些结果表明，gp 120诱导海马神经元凋亡的增强Ik，这可能与增加Kv2.1表达通过p38 MAPK途径。
Human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein 120 (gp120) has been reported to be toxic to the hippocampal neurons, and to be involved in the pathogenesis of HIV-1-associated neurocognitive disorders (HAND). Accumulating evidence has demonstrated that voltage-gated potassium (Kv) channels, especially the outward delayed-rectifier K(+) (Ik) channels, play a critical role in gp120-induced cortical neuronal death in vitro. However, the potential mechanisms underlying the hippocampal neuronal injury resulted from gp120-mediated neurotoxicity remain poorly understood. Using whole-cell patch clamp recording in cultured hippocampal neurons, this study found that gp120 significantly increased the outward delayed-rectifier K(+) currents (Ik). Meanwhile, Western blot assay revealed that gp120 markedly upregulated Kv2.1 protein levels, which was consistent with the increased Ik density. With Western blot and terminal deoxynucleotidyl transferase dUTP nick end labeling assays, it was discovered that gp120-induced neuronal injury was largely due to activation of Kv2.1 channels and resultant apoptosis mediated by caspase-3 activation, as the pharmacological blockade of Kv2.1 channels largely attenuated gp120-induced cell damage and caspase-3 expression. Moreover, p38 MAPK was demonstrated to participate in gp120-induced hippocampal neural damage, since p38 MAPK antagonist (SB203580) partially abrogated gp120-induced Kv2.1 upregulation and neural apoptosis. Taken together, these results suggest that gp120 induces hippocampal neuron apoptosis by enhancement of the Ik, which might be associated with increased Kv2.1 expression via the p38 MAPK pathway.
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