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Vol. 53, Issue 5, 933-941, May 1998
Department of Pharmacology, University of Pennsylvania
School of Medicine, Philadelphia, Pennsylvania (K.W., A.J.P., N.D.N.),
and
Faculty of Pharmaceutical Sciences, Chiba University, Chiba, Japan
(K.K., T.M., K.I.)
A hallmark feature of N-methyl-D-aspartate
(NMDA) receptors is their voltage-dependent block by extracellular
Mg2+. The structural basis for Mg2+ block is
not fully understood. Although asparagine residues in the pore-forming
M2 regions of NR1 and NR2 subunits influence Mg2+ block, it
has been speculated that additional residues are likely to be involved.
Here, we report the unexpected finding that a tryptophan residue in the
M2 region of NR2 subunits controls Mg2+ block. An
NR2B(W607L) mutation abolished block and greatly increased permeation
of extracellular Mg2+. A similar effect was seen with a
mutation at the equivalent residue in NR2A but not with mutations at
the equivalent residue or adjacent residues in NR1. In NR2B, mutations
that changed NR2B(W607) to asparagine (W607N) or alanine (W607A) also
greatly reduced Mg2+ block, whereas mutations that changed
W607 to the aromatic residues tyrosine (W607Y) or phenylalanine (W607F)
had little or no effect on Mg2+ block. Furthermore, the
W607L, W607N, and W607A mutants, but not the W607Y and W607F mutants,
decreased Ba2+ permeability of NMDA channels. Thus, residue
NR2B(W607) may be involved in binding of divalent cations, in
particular Mg2+, through a cation-
interaction with the
electron-rich aromatic ring of the tryptophan. We previously suggested
that NR2B(W607) may contribute to the narrow constriction of the NMDA
channel. A model is now proposed in which the M2 loop of NR2B is folded in such a way that NR2B(W607) is positioned at the narrow constriction, at a level similar to NR2B(N616) and NR1(N616), with these three residues forming a binding site for Mg2+.
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