Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity
Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity
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DOI：
10.1073/pnas.95.24.14500
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发表时间：
1998-11-24
影响因子：
11.1
通讯作者：
Miller, RJ
中科院分区：
文献类型：
--
作者：
Meucci, O;Fatatis, A;Miller, RJ
HIV-1包膜蛋白gp120诱导海马神经元凋亡。由于趋化因子受体作为HIV-1的细胞受体，我们检查了大鼠海马神经元中是否存在功能性趋化因子受体。基于Fura-2的钙成像显示，包括SDF-1α、RANTES和Fractalkine在内的众多趋化因子影响神经元钙信号转导，提示海马神经元具有广泛的趋化因子受体。趋化因子也阻断了这些神经元记录的自发谷氨酸能兴奋性突触后电流的频率，并减少了这些神经元的电压依赖性钙电流。逆转录-聚合酶链式反应显示CCR1、CCR4、CCR5、CCR9/10、CXCR2、CXCR4和CX(3)CR1以及趋化因子Fractalkine在这些神经元中均有表达。Fractalkine和巨噬细胞衍生趋化因子(MDC)均能激活细胞外反应蛋白(ERK)-1/2，而不激活c-Jun NH2末端蛋白激酶(JNK)/应激激活蛋白激酶(P38)。此外，这两种趋化因子以及SDF-1α激活了依赖钙和cAMP的转录因子CREB。在胶质滋养层存在和不存在的情况下，几种趋化因子也能够阻断gp120诱导的海马神经元凋亡。这些数据表明趋化因子受体可能直接介导gp120的神经毒性。
The HIV-1 envelope protein gp120 induces apoptosis in hippocampal neurons. Because chemokine receptors act as cellular receptors for HIV-1, we examined rat hippocampal neurons for the presence of functional chemokine receptors. Fura-2-based Ca imaging showed that numerous chemokines, including SDF-1 alpha, RANTES, and fractalkine, affect neuronal Ca signaling, suggesting that hippocampal neurons possess a wide variety of chemokine receptors. Chemokines also blocked the frequency of spontaneous glutamatergic excitatory postsynaptic currents recorded from these neurons and reduced voltage-dependent Ca currents in the same neurons. Reverse transcription-PCR demonstrated the expression of CCR1, CCR4, CCR5, CCR9/10, CXCR2, CXCR4, and CX(3)CR1, as well as the chemokine fractalkine in these neurons. Both fractalkine and macrophage-derived chemokine (MDC) produced a time dependent activation of extracellular response kinases (ERK)-1/2, whereas no activation of c-JUN NH2-terminal protein kinase (JNK)/stress-activated protein kinase, or p38 was evident. Furthermore, these two chemokines, as well as SDF-1 alpha; activated the Ca-and cAMP-dependent transcription factor CREB. Several chemokines were able also to block gp120-induced apoptosis of hippocampal neurons, both in the presence and absence of the glial feeder layer. These data suggest that chemokine receptors may directly mediate gp120 neurotoxicity.