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Luoxiu Huang, Dao-Qi Zhang, Francis Castellino; Synthetic conantokin peptides potently inhibit NMDA receptor-mediated currents of retinal ganglion cells. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3406.
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The synthetic conantokin peptides (con-G and con-T) are small γ-carboxyglutamate (Gla)-containing gene products present in snails of the genus, Conus. These peptides have been shown to be neruoprotective in a number of animal models of human pathologies, including pain, convulsive disorders, stroke, and Parkinson's disease. However, it is unknown whether they have neuroprotective action on retinal neurodegenerative diseases such as glaucoma. Towards this end, we sought to examine effects of con-G and con-T on NMDA-mediated responses of mouse retinal ganglion cells (RGCs).
Transgenic mice (B6.Cg-Tg(Thy1-YFP)16Jrs/J) that express yellow fluorescent protein (YFP) in RGCs and bipolar cells were obtained from the Jackson Laboratory. Dissociated retina cells were obtained from mice approximately 2 mo of age and were viewed with a fluorescence microscope. YFP labeled RGCs were distinguished from the YFP-marked bipolar cells based on their large soma sizes and Na+-mediated currents (>200 pA). Whole cell patch-clamp recording was performed from the YFP-expressing RGCs after the cells were cultured for 2-8 hrs. Chemically syntheses of the conantokins for these studies was employed using an Applied Biosystems Model 433A peptide synthesizer.
NMDA receptor-mediated currents of RGCs were induced by 500 µM NMDA and 10 µM glycine (with 1 µM strychnine). Con-G and con-T (50 µM) reduced the steady-state currents to 43% and 16% of the control, respectively. These effects were dose-dependent with an IC50 of 7.34 µM for con-G and of 6.38 µM for con-T. In addition, con-G reduced the efficacy of NMDA by a decrease in the maximal current from 205 ± 30 pA to 79 ±22 pA. A similar result was obtained with con-T, suggesting both con-T and con-G inhibit NMDA-mediated currents in a noncompetitive manner.
Our results demonstrate that both con-G and con-T non-competitively inhibit NMDA receptor-mediated currents of retinal ganglion cells in a dose-dependent manner. The results provide a basis for potentially developing effective neuroprotective agents to aid in the prevention of undesired glutamatergic excitotoxicity in neurodegenerative diseases of the retina.
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