首页> 外文期刊>Journal of Neurochemistry: Offical Journal of the International Society for Neurochemistry >HIV-1 Tat activates a RhoA signaling pathway to reduce NMDA-evoked calcium responses in hippocampal neurons via an actin-dependent mechanism
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HIV-1 Tat activates a RhoA signaling pathway to reduce NMDA-evoked calcium responses in hippocampal neurons via an actin-dependent mechanism

机译:HIV-1 Tat通过肌动蛋白依赖性机制激活RhoA信号通路以减少海马神经元中NMDA引起的钙反应

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摘要

HIV-associated neurocognitive disorders afflict approximately half of HIV-infected patients. HIV-infected cells within the CNS release neurotoxic viral proteins such as the transactivator of transcription (Tat). Tat caused a biphasic change in NMDAR function; NMDA-evoked increases in intracellular Ca2+ were initially potentiated following 16h exposure to Tat and then adapted by gradually returning to baseline by 24h. Following Tat-induced NMDAR potentiation, a RhoA/Rho-associated protein kinase (ROCK) signaling pathway was activated; a subsequent remodeling of the actin cytoskeleton reduced NMDA-evoked increases in intracellular Ca2+. Pharmacologic or genetic inhibition of RhoA or ROCK failed to affect potentiation, but prevented adaptation of NMDAR function. Activation of RhoA/ROCK signaling increases the formation of filamentous actin. Drugs that prevent changes to filamentous actin blocked adaptation of NMDAR function following Tat-induced potentiation, whereas stimulating either depolymerization or polymerization of actin attenuated NMDAR function. These findings indicate that Tat activates a RhoA/ROCK signaling pathway resulting in actin remodeling and subsequent reduction of NMDAR function. Adaptation of NMDAR function may be a mechanism to protect neurons from excessive Ca2+ influx and could reveal targets for the treatment of HIV-associated neurocognitive disorders.
机译:艾滋病毒相关的神经认知障碍折磨了大约一半的艾滋病毒感染患者。 CNS中感染HIV的细胞释放神经毒性病毒蛋白,例如转录反式激活因子(Tat)。 Tat引起NMDAR功能的两相变化; NMDA引起的细胞内Ca2 +的增加最初在暴露于Tat的16h后被增强,然后在24h逐渐恢复到基线来适应。 Tat诱导NMDAR增强后,RhoA / Rho相关蛋白激酶(ROCK)信号通路被激活。随后肌动蛋白细胞骨架的重塑减少了NMDA引起的细胞内Ca2 +的增加。 RhoA或ROCK的药理或遗传抑制作用无法影响增强作用,但阻止了NMDAR功能的适应性。 RhoA / ROCK信号的激活增加了丝状肌动蛋白的形成。防止丝状肌动蛋白变化的药物会在达特诱导的增强作用后阻止NMDAR功能的适应,而刺激肌动蛋白的解聚或聚合会减弱NMDAR功能。这些发现表明,Tat激活RhoA / ROCK信号传导途径,导致肌动蛋白重塑并随后降低NMDAR功能。 NMDAR功能的适应可能是保护神经元免受过多Ca2 +流入的一种机制,并且可能揭示治疗HIV相关神经认知障碍的靶标。

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