Wu Jun, Holstein J Deborah, Upadhyay Geeta, Lin Da-Ting, Conway Stuart, Muller Elizabeth, Lechleiter James D
Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA.
J Neurosci. 2007 Jun 13;27(24):6510-20. doi: 10.1523/JNEUROSCI.1256-07.2007.
Astrocytes play an essential role in the maintenance and protection of the brain, which we reported was diminished with age. Here, we demonstrate that activation of a purinergic receptor (P2Y-R) signaling pathway, in astrocytes, significantly increases the resistance of astrocytes and neurons to oxidative stress. Interestingly, P2Y-R activation in old astrocytes increased their resistance to oxidative stress to levels that were comparable with stimulated young astrocytes. P2Y-R enhanced neuroprotection was blocked by oligomycin and by Xestospongin C, inhibitors of the ATP synthase and of inositol (1,4,5) triphosphate (IP3) binding to the IP3 receptor, respectively. Treatment of astrocytes with a membrane permeant analog of IP3 also protected astrocytes against oxidative stress. These data indicate that P2Y-R enhanced astrocyte neuroprotection is mediated by a Ca2+-dependent increase in mitochondrial metabolism. These data also reveal a signaling pathway that can rapidly respond to central energy needs throughout the aging process.
星形胶质细胞在大脑的维持和保护中发挥着重要作用,我们之前报道过其功能会随着年龄增长而减弱。在此,我们证明,星形胶质细胞中嘌呤能受体(P2Y-R)信号通路的激活显著增强了星形胶质细胞和神经元对氧化应激的抗性。有趣的是,老年星形胶质细胞中P2Y-R的激活将其对氧化应激的抗性提高到了与受刺激的年轻星形胶质细胞相当的水平。P2Y-R增强的神经保护作用分别被寡霉素和西司他汀C阻断,寡霉素是ATP合酶的抑制剂,西司他汀C是肌醇(1,4,5)三磷酸(IP3)与IP3受体结合的抑制剂。用IP3的膜渗透性类似物处理星形胶质细胞也能保护其免受氧化应激。这些数据表明,P2Y-R增强的星形胶质细胞神经保护作用是由线粒体代谢中Ca2+依赖性增加介导的。这些数据还揭示了一条在整个衰老过程中能快速响应中枢能量需求的信号通路。