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Journal of Neuroscience, Vol 14, 5471-5484, Copyright © 1994 by Society for Neuroscience
The molecular basis of NMDA receptor subtypes: native receptor diversity is predicted by subunit composition
AL Buller, HC Larson, BE Schneider, JA Beaton, RA Morrisett and DT Monaghan
Department of Pharmacology, University of Nebraska Medical Center, Omaha 68198-6260.
The relationship between four pharmacologically distinct NMDA receptor
subtypes, identified in radioligand binding studies, and the recently
identified NMDA receptor subunits (NR1a-g, NR2A-D) has not been determined.
In this report, we demonstrate that the anatomical distribution of the four
NMDA receptor subtypes strikingly parallels the distribution of mRNA
encoding NR2A-D subunits. The distribution of NR2A mRNA was very similar to
that of "antagonist-preferring" NMDA receptors [defined by high-affinity
3H-2-carboxypiperazine-4-yl-propyl- 1-phosphonic (3H-CPP) binding sites;
correlation coefficient = 0.88]. Agonist-preferring NMDA receptors
localized to brain regions expressing both NR2B mRNA and NR1- mRNA (NR1
splice variant lacking insert 1). NR2C mRNA was largely restricted to the
cerebellar granule cell layer, a region that displays a unique
pharmacological profile. NR2D mRNA localized exclusively to those
diencephalic nuclei that have a fourth, distinct pharmacological profile
(typified by the midline thalamic nuclei). The pharmacology of native NMDA
receptors was compared to that of heteromeric NMDA receptors expressed in
Xenopus oocytes (NR1/NR2A, NR1/NR2B, NR1/NR2C). The oocyte-expressed
NR1/NR2A receptor displayed a higher affinity for antagonists and a
slightly lower affinity for agonists than the NR1/NR2B receptor. These
patterns are analogous to those found for radioligand binding to native
receptors in the lateral thalamus and medial striatum, respectively. NMDA
receptors in the lateral thalamus (with a high density of NR2A subunit
mRNA) displayed higher affinity for antagonists and a lower affinity for
agonists than did NMDA receptors of the medial striatum (a region rich in
NR2B mRNA). Relative to the NR1/NR2A and NR1/NR2B receptors,
oocyte-expressed NR1/NR2C receptors had a lower affinity specifically for
both D-3-(2- carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid (D-CPPene)
and homoquinolinate (HQ). This pattern was identical to that observed for
cerebellar (NR2C-containing) versus forebrain (NR2A- and NR2B- containing)
NMDA receptors. Taken together, the data in this report suggest that the
four previously identified native NMDA receptor subtypes differ in their
NR2 composition. Furthermore, the NR2 subunits significantly contribute to
the anatomical and pharmacological diversity of NMDA receptor subtypes.
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