Purinergic receptor-stimulated IP3-mediated Ca2+ release enhances neuroprotection by increasing astrocyte mitochondrial metabolism during aging.
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.
Wu
Jun
J
Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA.
Holstein
J Deborah
JD
Upadhyay
Geeta
G
Lin
Da-Ting
DT
Conway
Stuart
S
Muller
Elizabeth
E
Lechleiter
James D
JD
D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000648:ultrastructure*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D047028:Macrocyclic Compounds / Q000494:pharmacology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D009840:Oligomycins / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010101:Oxygen Consumption / Q000502:physiology; D011983:Receptors, Purinergic / Q000502:physiology*; D013997:Time Factors
D004791:Enzyme Inhibitors; D047028:Macrocyclic Compounds; D009840:Oligomycins; D010080:Oxazoles; D011983:Receptors, Purinergic; C511704:xestospongin C; D015544:Inositol 1,4,5-Trisphosphate; D000255:Adenosine Triphosphate; D002118:Calcium