Dj. Laurie et Ph. Seeburg, LIGAND AFFINITIES AT RECOMBINANT N-METHYL-D-ASPARTATE RECEPTORS DEPEND ON SUBUNIT COMPOSITION, European journal of pharmacology. Molecular pharmacology section, 268(3), 1994, pp. 335-345
The ligand preferences of recombinant NR1 homomeric and NR1-NR2 hetero
meric NMDA receptors were examined by homogenate binding assay. The bi
nding affinities for most ligands were similar to those reported for n
ative NMDA receptors. The order of affinity for [H-3]glutamate was NR1
-NR2B > NR1-NR2A approximate to NR1-NR2D > NR1-NR2C > NR1. NMDA had ap
proximately equal affinity for all heteromeric types (K-i approximate
to 5 mu M), but the competitive antagonists CGS 19755 (cis-4-(phosphon
omethyl)piperidine-2-carboxylic acid) and CGP 39653 (D,L-(E)-2-amino-4
-propyl-5-phosphono-3-pentenoic acid) displayed the affinity order NR1
-NR2A > NR1-NR2B > NR1-NR2D > NR1-NR2C. Binding of [H-3]CGP 39653 coul
d only be detected at the NR1-NR2A receptor type (K-d approximate to 6
nM). The glycine site antagonist [H-3]5,7-dichlorokynurenate bound wi
th good affinity to all recombinant receptors (K-d approximate to 50-1
00 nM), while glycine exhibited an affinity order of NR1-NR2C >> NR1 =
NR1-NR2B = NR1-NR2D > NR1-NR2A. The channel-site ligand [H-3]MK 801 (
(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] 5,10-imine hydrogen maleate
) showed the affinity ranking NR1-NR2A = NR1-NR2B >> NR1 > NR1-NR2C =
NR1-NR2D. Thus the ligand binding affinities of recombinant NMDA recep
tors is dependent on their subunit composition. The NR1-NR2A, NR1-NR2B
, NR1-NR2C and NR1-NR2D receptors may account for the antagonist-prefe
rring, agonist-preferring, cerebellar, and medial thalamic subtypes of
native NMDA receptors, respectively.