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Yong-Mei Zhong, Xin-Jun Zhang, Lei-Lei Liu, Xiong-Li Yang; Signaling Pathway Mediating Suppression of NMDA Responses of Rat Retinal Ganglion Cells by Activation of the Sigma Receptor 1. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4577.
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© ARVO (1962-2015); The Authors (2016-present)
The sigma receptor 1 (σR1) is known to protect retinal neurons from damage in both in vitro and in vivo models, but the underlying mechanisms are poorly understood. This study is aimed to examine effects of σR1 activation on NMDA receptor mediated currents, light evoked excitatory postsynaptic currents (EPSCs) of retinal ganglion cells (RGCs) and to explore possible signaling pathways involved in the effects.
Experiments were conducted in rat retinal slice preparations using whole cell patch-clamp techniques, combined with pharmacological methods.
Activation of σR1 by SKF10047 (SKF) or PRE-084 suppressed NMDA currents from both ON and OFF type RGCs dose-dependently, and the effect could be blocked by the σR1 antagonists. The suppression by SKF of NMDA currents was abolished with pre-incubation of the G protein inhibitor GDP-β-S or the Gi/o activator mastoparan. Application of either cAMP/the PKA inhibitor or cGMP/the PKG inhibitor did not change the SKF-induced effect, suggesting no involvement of cAMP/PKA and cGMP/PKG pathways. In contrast, suppression of NMDA currents by SKF was abolished by internal infusion of the phosphatidylinostiol (PI)-specific phospholipase C (PLC) inhibitor U73122, but not by the phosphatidylcholine (PC)-PLC inhibitor D609. SKF-induced suppression of NMDA currents was calcium dependent, and it was blocked by xestospongins-C/heparin, IP3 receptor antagonists, but unchanged by ryanodine/caffeine, ryanodine receptor modulators. Furthermore, application of PKC inhibitors Bis IV and Gö6976 eliminated the SKF effect. Consistently, bath application of SKF suppressed light evoked NMDA receptor mediated EPSCs in ON, OFF and ON-OFF RGCs, but did not affect AMPA receptor mediated miniature EPSCs, suggesting a direct action of SKF on RGCs.
Activation of σR1 suppresses NMDA receptor mediated currents and light evoked EPSCs, which is mediated by a distinct [Ca2+]i-dependent PI-PLC-PKC pathway. Such suppression provides a possible explanation for the neuroprotective role of σR1 in the retina.
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