Two classes of N-methyl-D-aspartate recognition sites: differential distribution and differential regulation by glycine.
The N-methyl-D-aspartate (NMDA) receptor, a subtype of excitatory amino acid receptor, mediates synaptic responses in many regions of the central nervous system. This receptor plays a critical role in the mechanisms of both synaptic plasticity and excitotoxicity. Although these receptors were generally thought to be a single homogeneous receptor population, we report observations indicating that two anatomically distinct forms of the NMDA-receptor complex exist. (i) The distribution of NMDA receptors, as labeled by the NMDA agonist L-[3H]glutamate, differs from that obtained with the radiolabeled antagonist 3H-labeled 3-[(+/-)2-carboxypiperazine-4-yl]propyl-1-phosphonic acid [( 3H]CPP). Relative to L-[3H]glutamate, [3H]CPP binding is low in the striatum and septum and high in the thalamus and inner cerebral cortex. (ii) NMDA antagonists are relatively more potent than agonists at displacing L-[3H]glutamate binding in the thalamus and cerebral cortex; agonists are relatively more potent in the striatum and cerebellum. (iii) Glycine, which potentiates NMDA-receptor responses to glutamate, causes a greater percentage increase in L-[3H]glutamate binding to NMDA receptors in the thalamus and cerebral cortex than in the striatum, septum, and cerebellum. Radiolabeled NMDA-antagonist binding, in contrast, is inhibited by glycine. Thus, as observed for gamma-aminobutyric acid type A receptors, NMDA receptors have an agonist-preferring binding-site population and an antagonist-preferring binding site population. These may represent two distinct receptors and/or two interconverting forms. It could be of significant clinical importance if these two sites differ in their response to NMDA.
Monaghan
D T
DT
Division of Neurosurgery, University of California, Irvine 92717.
Olverman
H J
HJ
Nguyen
L
L
Watkins
J C
JC
Cotman
C W
CW
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D001345:Autoradiography; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D005998:Glycine / Q000494:pharmacology*; D008297:Male; D016202:N-Methylaspartate; D010879:Piperazines; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000378:metabolism / Q000493:pharmacokinetics*
D005971:Glutamates; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D001224:Aspartic Acid; D018698:Glutamic Acid; D016202:N-Methylaspartate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D005998:Glycine