Modulation of N-methyl-D-aspartate receptor function by glycine transport

The recent discovery of glycine transporters in both the central nervous sy stem and the periphery suggests that glycine transport may be critical to N -methyl-D-aspartate receptor (NMDAR) function by controlling glycine concen tration at the NMDAR modulatory glycine site. Data obtained from whole-cell patch-clamp recordings of hippocampal pyramidal neurons, in vitro, demonst rated that exogenous glycine and glycine transporter type 1 (GLYT1) antagon ist selectively enhanced the amplitude of the NMDA component of a glutamate rgic excitatory postsynaptic current. The effect was blocked by 2-amino-5-p hosphonovaleric acid and 7-chloro-kynurenic acid but not by strychnine, Thu s, the glycine-binding site was not saturated under the control conditions. Furthermore, GLYT1 antagonist enhanced NMDAR function during perfusion wit h medium containing 10 mu M glycine, a concentration similar to that in the cerebrospinal fluid in vivo, thereby supporting the hypothesis that the GL YT1 maintains subsaturating concentration of glycine at synaptically activa ted NMDAR. The enhancement of NMDAR function by specific GLYT1 antagonism m ay be a feasible target for therapeutic agents directed toward diseases rel ated to hypofunction of NMDAR.