RT Journal Article
SR Electronic
T1 Interactions between the glycine and glutamate binding sites of the NMDA receptor
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 1088
OP 1096
DO 10.1523/JNEUROSCI.13-03-01088.1993
VO 13
IS 3
A1 RA Lester
A1 G Tong
A1 CE Jahr
YR 1993
UL http://www.jneurosci.org/content/13/3/1088.abstract
AB The interactions between the glycine and glutamate binding sites of the NMDA receptor have been studied in outside-out patches and synapses from hippocampal neurons in culture using rapid drug application techniques. Desensitization of NMDA receptor-mediated currents elicited by glutamate in newly excised outside-out patches was reduced in the presence of saturating concentrations of glycine. This suggests that the glutamate and glycine binding sites of the NMDA receptor are allosterically coupled as has been reported in whole-cell preparations. A glycine-insensitive form of desensitization increased rapidly over the first few minutes of recording and largely occluded the glycine concentration-sensitive desensitization in outside-out patches. However, even in old patches that displayed no glycine-sensitive desensitization, the unbinding rate of glycine was increased fourfold by the presence of glutamate, suggesting that the two binding sites were still allosterically coupled. These data suggest the existence of two forms of NMDA receptor desensitization in outside-out patches, only one of which is dependent on the concentration of glycine. In the presence of saturating levels of glycine, activation of NMDA receptors by synaptic stimulation or by exogenous glutamate resulted in currents that relaxed biexponentially. Addition of the partial glycine-site agonist 1-hydroxy-3-aminopyrrolid-2-one (HA-966) increased the rate of decay of both synaptic and patch currents. This suggests that HA-966 increases the dissociation rate of glutamate from NMDA receptors. These results support the hypothesis that the glutamate and glycine binding sites of NMDA receptors interact allosterically; ligand binding at both types of sites can affect the affinity of the other type for its agonist.