THE MOLECULAR-BASIS OF NMDA RECEPTOR SUBTYPES - NATIVE RECEPTOR DIVERSITY IS PREDICTED BY SUBUNIT COMPOSITION

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 deter mined. In this report, we demonstrate that the anatomical distribution of the four NMDA receptor subtypes strikingly parallels the distribut ion of mRNA encoding NR2A-D subunits. the distribution of NR2A mRNA wa s very similar to that of ''antagonist-preferring'' NMDA receptors [de fined by high-affinity H-3-2-carboxypiperazine-4-yl-propyl-1-phosphoni c (H-3-CPP) binding sites; correlation coefficient = 0.88]. Agonist-pr eferring NMDA receptors localized to brain regions expressing both NR2 8 mRNA and NR1- mRNA (NR1 splice variant lacking insert 1). NRSC mRNA was largely restricted to the cerebellar granule cell layer, a region that displays a unique pharmacological profile. NR2D mRNA localized ex clusively to those diencephalic nuclei that have a fourth, distinct ph armacological profile (typified by the midline thalamic nuclei). The p harmacology of native NMDA receptors was compared to that of heteromer ic NMDA receptors expressed in Xenopus oocytes (NR1/NRSA, NR1/NRSB, NR 1/NRPC). The oocyte-expressed NR1/NRSA receptor displayed a higher aff inity for antagonists and a slightly lower affinity for agonists than the NR1/NRSB receptor. These patterns are analogous to those found for radioligand binding to native receptors in the lateral thalamus and m edial striatum, respectively NMDA receptors in the lateral thalamus (w ith 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 h ad a lower affinity specifically for both D-3-(2-carboxypiperarin-4-yl )-1-propenyl-1 -phosphonic acid (D-CPPene) and homoquinolinate (HQ). T his pattern was identical to that observed for cerebellar (NRPC-contai ning) versus forebrain (NR2A- and NR2B-containing) NMDA receptors. Tak en together, the data in this report suggest that the four previously identified native NMDA receptor subtypes differ in their NR2 compositi on. Furthermore, the NR2 subunits significantly contribute to the anat omical and pharmacological diversity of NMDA receptor subtypes.