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H. Hu, M. Zhang, W. Lu, D. Reigada, A. M. Laties, X. Zhang, C. H. Mitchell; Activation of the P2X7 Receptor on Retinal Ganglion Cells Delivers Glutamate and Relieves the Mg2+ Block to Activate the NMDA Receptor. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5950.
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Stimulation of the P2X7 receptor for ATP can kill retinal ganglion cells. Cell death is prevented by the NMDA antagonists NMDA, APV and memantine, implying involvement of the NMDA receptor. Stimulation of the P2X7 receptor causes a release of glutamate from isolated ganglion cells, consistent with the downstream involvement of NMDA receptors. We hypothesize that activation of the P2X7 receptor also depolarizes the ganglion cell, relieving the voltage-dependent block of the NMDA channel by Mg2+. This study investigated the relationship between the NMDA receptor, the P2X7 receptor and Mg2+.
Intracellular calcium measurements were made from unlabeled isolated immunopanned rat pup retinal ganglion cells cultured for 24 h and loaded with fura-2. Cell viability was assessed by determining the percentage of labeled ganglion cells present after 24 h culture with drugs. NMDA was always given with co-factor glycine.
In the absence of Mg2+, NMDA stimulated a Ca2+ elevation in 92% of retinal ganglion cells. Addition of physiologic levels of Mg2+ (0.5 mM) eliminated the Ca2+ elevation in response to NMDA. However, MK-801 substantially inhibited the Ca2+ transient evoked after stimulation of the P2X7 receptor in the presence of Mg2+, suggesting the channel could open if the P2X7 receptor was activated first. This was supported by the inability of NMDA alone to kill cells, while MK-801 stopped the cell death triggered by P2X7 receptor agonist BzATP. The independence of the two receptors was determined pharmacologically, with Brilliant Blue G inhibiting the response to BzATP, but having no effect on the response to NMDA. The response to P2X7 receptor activation was reduced by bafilomycin-A, consistent with a vesicular release of glutamate.
This study suggests that stimulation of the P2X7 receptor releases glutamate and depolarizes the membrane to relieve the Mg2+ block of the NMDA receptor. This one-two combination would make the P2X7 receptor well positioned to activate the NMDA receptor under conditions of either potentiation or excitotoxicity.
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