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Vol. 55, Issue 6, 957-969, June 1999
Department of Pharmacology, University of Pennsylvania School of
Medicine, Philadelphia, Pennsylvania (N.D.N., A.J.P., K.W.); and
Faculty of Pharmaceutical Sciences, Chiba University, Chiba, Japan
(T.M., K.K., T.K., J.F., K.I.)
There are complex interactions between spermine, protons, and
ifenprodil at N-methyl-D-aspartate
receptors. Spermine stimulation may involve relief of proton
inhibition, whereas ifenprodil inhibition may involve an increase in
proton inhibition. We studied mutations at acidic residues in the NR1
subunit using voltage-clamp recording of NR1/NR2B receptors expressed
in Xenopus oocytes. Mutations at residues near the site
of the exon-5 insert, including E181 and E185, reduced spermine
stimulation and proton inhibition. Mutation NR1(D130N) reduced
sensitivity to ifenprodil by more than 500-fold, but had little effect
on sensitivity to spermine and pH. Mutations at six other residues in
this region of the NR1 subunit reduced the potency and, in some cases,
the maximum effect of ifenprodil. These mutants did not affect
sensitivity to pH, glutamate, glycine, or other hallmark properties of
N-methyl-D-aspartate channels such as
Mg2+ block and Ba2+ permeability. Residues in
this region presumably form part of the ifenprodil-binding site. To
model this region of NR1 we compared the predicted secondary structure
of NR1 (residues 19-400) with the known structures of 1,400 proteins.
This region of NR1 is most similar to bacterial
leucine/isoleucine/valine binding protein, a globular amino acid
binding protein containing two lobes, similar to the downstream S1-S2
region of glutamate receptors. We propose that the tertiary structure
of NR1(22-375) is similar to leucine/isoleucine/valine binding
protein, containing two "regulatory" domains, which we term R1 and
R2. This region, which contains the binding sites for spermine and
ifenprodil, may influence the downstream S1 and S2 domains that
constitute the glycine binding pocket.
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