title: Critical involvement of extracellular ATP acting on P2RX7 purinergic receptors in photoreceptor cell death.
abstract: Stressed cells release ATP, which participates in neurodegenerative processes through the specific ligation of P2RX7 purinergic receptors. Here, we demonstrate that extracellular ATP and the more specific P2RX7 agonist, 2'- and 3'-O-(4-benzoylbenzoyl)-ATP, both induce photoreceptor cell death when added to primary retinal cell cultures or when injected into the eyes from wild-type mice, but not into the eyes from P2RX7(-/-) mice. Photoreceptor cell death was accompanied by the activation of caspase-8 and -9, translocation of apoptosis-inducing factor from mitochondria to nuclei, and TUNEL-detectable chromatin fragmentation. All hallmarks of photoreceptor apoptosis were prevented by premedication or co-application of Brilliant Blue G, a selective P2RX7 antagonist that is already approved for the staining of internal limiting membranes during ocular surgery. ATP release is up-regulated by nutrient starvation in primary retinal cell cultures and seems to be an initializing event that triggers primary and/or secondary cell death via the positive feedback loop on P2RX7. Our results encourage the potential application of Brilliant Blue G as a novel neuroprotective agent in retinal diseases or similar neurodegenerative pathologies linked to excessive extracellular ATP.
authors: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Shoji
authors: S
authors: Notomi
authors: Toshio
authors: T
authors: Hisatomi
authors: Takaaki
authors: T
authors: Kanemaru
authors: Atsunobu
authors: A
authors: Takeda
authors: Yasuhiro
authors: Y
authors: Ikeda
authors: Hiroshi
authors: H
authors: Enaida
authors: Guido
authors: G
authors: Kroemer
authors: Tatsuro
authors: T
authors: Ishibashi
mesh_terms: D000255:Adenosine Triphosphate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D053222:Fas Ligand Protein / Q000494:pharmacology; D007202:Indicators and Reagents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010786:Photoreceptor Cells / Q000473:pathology*; D058911:Purinergic P2X Receptor Agonists / Q000494:pharmacology; D058486:Receptors, Purinergic P2X7 / Q000187:drug effects*; D012162:Retinal Degeneration / Q000473:pathology; D012394:Rosaniline Dyes / Q000008:administration & dosage / Q000494:pharmacology*; D013312:Stress, Physiological; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D053222:Fas Ligand Protein; D007202:Indicators and Reagents; D058911:Purinergic P2X Receptor Agonists; D058486:Receptors, Purinergic P2X7; D012394:Rosaniline Dyes; D014409:Tumor Necrosis Factor-alpha; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate; D053181:Caspase 8; C004692:coomassie Brilliant Blue; D002118:Calcium