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The Journal of Neuroscience, June 13, 2007, 27(24):6510-6520; doi:10.1523/JNEUROSCI.1256-07.2007

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Cellular/Molecular
Purinergic Receptor-Stimulated IP₃-Mediated Ca²⁺ Release Enhances Neuroprotection by Increasing Astrocyte Mitochondrial Metabolism during Aging

Jun Wu, J. Deborah Holstein, Geeta Upadhyay, Da-Ting Lin, Stuart Conway, Elizabeth Muller, and James D. Lechleiter

Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900

Correspondence should be addressed to Dr. James D. Lechleiter, Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900. Email: lechleiter{at}uthscsa.edu

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.

Key words: intracellular Ca²⁺; mitochondria; IP₃; P2Y-R; two-photon; metabolism

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Received June 2, 2006; revised April 24, 2007; accepted April 25, 2007.

Correspondence should be addressed to Dr. James D. Lechleiter, Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900. Email: lechleiter{at}uthscsa.edu

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