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Stimulation of P2X₇ Receptors Elevates Ca²⁺ and Kills Retinal Ganglion Cells

¹From the Departments of Ophthalmology and ³Physiology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and the ²Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Peoples Republic of China.

PURPOSE. Retinal ganglion cells are known to express ionotropic P2X₇ receptors for ATP. Stimulation of these receptors in other cells can elevate Ca²⁺ and sometimes lead to cell death. This study asked whether P2X₇ receptor stimulation alters the Ca²⁺ levels and viability of retinal ganglion cells.

METHODS. P2X₇ agonists were applied to retinal ganglion cells from neonatal rats loaded with fura-2 to examine their effect on intracellular Ca²⁺ levels. The effect of P2X₇ receptor stimulation on cell viability was examined in rat retinal ganglion cells back-labeled with aminostilbamidine.

RESULTS. The P2X₇ agonist benzoylbenzoyl adenosine triphosphate (BzATP) led to a large, sustained increase in Ca²⁺. BzATP was >100-fold more effective than ATP at raising intracellular Ca²⁺, when both agonists were applied at 10 µM. The response to BzATP was enhanced threefold by removal of extracellular Mg²⁺, was dependent on extracellular Ca²⁺, and was prevented by brilliant blue G (BBG). BzATP led to a concentration-dependent reduction in the number of cells with a median lethal dose (LD₅₀) of 35 µM. Cell death was prevented by the P2X₇ antagonists BBG and oxidized ATP, but not by 30 µM suramin, consistent with the actions of the P2X₇ receptor. BzATP activated caspases in ganglion cells, but did not lead to membrane blebbing or increased permeability to Yo-Pro-1. The L-type Ca²⁺ channel blocker nifedipine attenuated cell death, suggesting excessive Ca²⁺ influx contributes to the lethal effects of BzATP.

CONCLUSION. Short-term stimulation of the P2X₇ receptor can raise Ca²⁺ in rat retinal ganglion cells, whereas sustained stimulation of the receptor can kill them.

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