Chemokine co-receptor CCR5/CXCR4-dependent modulation of Kv2.1 channel confers acute neuroprotection to HIV-1 glycoprotein gp120 exposure.
Chemokine co-receptor CCR5/CXCR4-dependent modulation of Kv2.1 channel confers acute neuroprotection to HIV-1 glycoprotein gp120 exposure.
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DOI：
10.1371/journal.pone.0076698
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Mohapatra DP
中科院分区：
文献类型：
--
作者：
Shepherd AJ;Loo L;Mohapatra DP
人类免疫缺陷病毒-1 （HIV-1）在大脑内的感染长期以来被认为与神经变性和神经认知障碍（HAND）有关，这种疾病的早期特征是认知功能下降和行为障碍。在机制上，HIV-1外壳糖蛋白120 （gp120）被认为是慢性暴露于病毒后，通过激活p38丝裂原活化蛋白激酶（MAPK），诱导神经元细胞凋亡的关键因素。本研究表明，急性暴露于HIV-1 gp120的神经元引发了一种稳态反应，该反应提供了对非凋亡细胞死亡的保护，涉及主要的体树突电压门控K+ (Kv)通道Kv2.1作为关键介质。Kv2.1通道最近被证明在癫痫发作、缺血和神经调节/神经炎症条件下提供神经元兴奋性的稳态控制。急性暴露于gp120后，培养的大鼠海马神经元表现出Kv2.1蛋白的快速去磷酸化，最终导致Kv2.1特异性亚细胞定位和电压依赖性通道激活特性的改变。Kv2.1中的这种修饰依赖于趋化因子共受体CCR5和CXCR4的激活，以及随后蛋白磷酸酶钙调磷酸酶的激活。这导致神经元兴奋性的全面抑制，并为神经元提供了一种稳态保护机制。特异性阻断钙调磷酸酶和Kv2.1通道活性导致急性gp120治疗后非凋亡神经元死亡显著增强。这些观察结果揭示了神经hiv感染急性期神经元恢复力的内在稳态机制。
Infection with human immunodeficiency virus-1 (HIV-1) within the brain has long been known to be associated with neurodegeneration and neurocognitive disorder (referred as HAND), a condition characterized in its early stages by declining cognitive function and behavioral disturbances. Mechanistically, the HIV-1 coat glycoprotein 120 (gp120) has been suggested to be a critical factor inducing apoptotic cell death in neurons via the activation of p38 mitogen-activated protein kinase (MAPK), upon chronic exposure to the virus. Here we show that acute exposure of neurons to HIV-1 gp120 elicits a homeostatic response, which provides protection against non-apoptotic cell death, involving the major somatodendritic voltage-gated K+ (Kv) channel Kv2.1 as the key mediator. The Kv2.1 channel has recently been shown to provide homeostatic control of neuronal excitability under conditions of seizures, ischemia and neuromodulation/neuroinflammation. Following acute exposure to gp120, cultured rat hippocampal neurons show rapid dephosphorylation of the Kv2.1 protein, which ultimately leads to changes in specific sub-cellular localization and voltage-dependent channel activation properties of Kv2.1. Such modifications in Kv2.1 are dependent on the activation of the chemokine co-receptors CCR5 and CXCR4, and subsequent activation of the protein phosphatase calcineurin. This leads to the overall suppression of neuronal excitability and provides neurons with a homeostatic protective mechanism. Specific blockade of calcineurin and Kv2.1 channel activity led to significant enhancement of non-apoptotic neuronal death upon acute gp120 treatment. These observations shed new light on the intrinsic homeostatic mechanisms of neuronal resilience during the acute stages of neuro-HIV infections.
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DOI：
10.1073/pnas.96.14.8212
发表时间：
1999-07-06
影响因子：
11.1
作者：
Kaul, M;Lipton, SA
通讯作者：
Lipton, SA
影响因子：
5.5
作者：
Guan, D.;Tkatch, T.;Foehring, R. C.
通讯作者：
Foehring, R. C.
影响因子：
9.2
作者：
Hesselgesser, J;Taub, D;Horuk, R
通讯作者：
Horuk, R
影响因子：
4.4
作者：
Grovit-Ferbas, K.;Harris-White, M. E.
通讯作者：
Harris-White, M. E.
影响因子：
6.4
作者：
Lipton, Stuart A.
通讯作者：
Lipton, Stuart A.