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E.C. Gustafson, E.R. Stevens, R.F. Miller; Glycine Transporters Enable D–Serine Modulation of NMDARs Currents in the Retina . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5391.
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Activation of the NMDA receptor requires the simultaneous binding of glutamate and a second coagonist, either glycine or D–serine. D–serine and its synthesizing enzyme, serine racemase (SR), have been discovered in the retina, raising the possibility that D–serine acts as the coagonist for retinal NMDARs. Given the relatively low levels of D–serine and high levels of glycine in the retina, the nature of occupancy at the coagonist site of retinal NMDARs needs to be further clarified. The glycine transporter type 1 (GlyT1) has been suggested to play a role in maintaining low levels of glycine in some regions rich in NMDARs. In the retina, GlyT1s seems to be limited to a subset of amacrine cells. Using electrophysiological techniques, we have investigated the role GlyT1s play in the unfolding story of coagonist action at the NMDARs of the retina.
Both extracellular (proximal negative response, PNR) and whole–cell recordings (WCR) from retinal ganglion cells (RGC) were used to examine if D–serine plays a functional role during light–evoked activity in the retina. Two D–serine degrading enzymes, D–amino acid oxidase (DAAO) and D–serine deaminase (DsDa), were added to the bathing media to decrease D–serine concentrations in retina–eyecup preparations during recordings. To examine the role of the glycine transporter on coagonist occupancy in the retina we used the GlyT1 specific blocker N[3–(4'–fluorophenyl)–3–(4'–phenylphenoxy)propyl]sarcosine (NFPS).
Addition of DAAO or DsDa resulted in a rapid, reversible decrease in light–induced NMDAR currents. Under normal conditions, adding exogenous D–serine to the bathing medium increases the light–induced currents generated by NMDARs. Following application of NFPS, a similar increase in NMDAR currents was measured, but subsequent addition of exogenous D–serine did not further enhance these NMDAR responses.
These results suggest that retinal GlyT1s are effective in insulating the NMDARs from saturating levels of glycine, thus enabling D–serine to have a functional role in modulating the currents generated by these receptors.
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