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E.R. Stevens, R.F. Miller; D-Serine Is More Effective than Glycine as a Co-Agonist at NMDA Receptors of Retinal Ganglion Cells . Invest. Ophthalmol. Vis. Sci. 2003;44(13):5136.
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Purpose: To determine the relative efficacy of D-serine and glycine as agonists at the glycine binding site of NMDA receptors in the vertebrate retina. Methods: Whole-cell recordings from ganglion cells in isolated wholemount retinal preparations from tiger salamander (Abystoma tigrinum) were performed to assess the relative roles of D-serine and glycine in contributing to NMDA receptor activation. Retinas were isolated from the sclera and pigment epithelium, and placed over a 2 mm hole in nitrocellulose filter paper, photoreceptors down. The gravity fed perfusion system delivered Ringer's solution and drugs to the preparation at 1-2 ml/min. Light stimulation was delivered to the tissue by illuminating a computer controlled LCD panel with a 12 V halogen source, and focusing the image through a water-immersion objective onto the plane of the retina. Low resistance micropipettes were guided to ganglion cells under infrared differential interference contrast microscopy. Brief pulses of NMDA were delivered to ganglion cells by a second micropipette placed near the recording electrode. Recordings were made with a Dagan 3900A amplifier (Dagan Instrument Co.), digitized using pClamp software (Axon Instruments), and analyzed in Origin (OriginLab Co.). Results: Exogenously applied D-serine potentiated both the ON and OFF component of ganglion cell light-evoked responses (130 micron slit of light centered on cell) at 10 to 100 times lower concentrations than glycine. This was also the case for responses to brief pulses of NMDA (1 mM in "puff" pipette). Furthermore, D-serine was more effective than glycine at overcoming a competitive block of the co-agonist site by 7-chloro-kynurenic acid. This hightened sensitivity to D-serine over glycine is at least 10-fold greater than has been reported in expression systems (e.g., Matsui, et. al, J. Neurochem. 1995). Studies are currently underway to determine whether this difference is a property of retinal NMDA receptors or a function of retinal processes such as glycine uptake. Conclusions: D-serine is much more effective as an agonist at the strychnine-insensitive glycine binding site of retinal ganglion cell NMDA receptors than is glycine. This raises the possibility that NMDA receptors preferentially utilize endogenous D-serine as a co-agonist in the vertebrate retina.
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