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Vol. 61, Issue 3, 595-605, March 2002
Molecular Neurobiology Laboratory, the Salk Institute, La Jolla,
California (B.V., S.F.H.); and the Vollum Institute, Oregon Health and
Science University, Portland, Oregon (J.J.K., G.L.W.)
At central excitatory synapses, the transient elevation of
intracellular calcium reduces
N-methyl-D-aspartate (NMDA) receptor activity. Such `calcium-dependent inactivation' is mediated by interactions of calcium/calmodulin and
-actinin with the C terminus of NMDA receptor 1 (NR1) subunit. However, inactivation is also NR2-subunit specific, because it occurs in NR2A- but not
NR2C-containing receptors. We examined the molecular basis for
NR2-subunit specificity using chimeric and mutated NMDA receptor
subunits expressed in HEK293 cells. We report that the intracellular
loop immediately distal to the pore-forming P-loop M2 (M2-3 loop), as
well as a short region in the C terminus, are involved in NR2-subunit
specificity. Within the M2-3 loop, substitution of residue 619 in NR2A
(valine) for the corresponding NR2C residue (isoleucine) reduced
inactivation without affecting calcium permeability of the channel. In
contrast, a Q620E mutation in NR2A reduced the relative calcium
permeability without altering inactivation. Mutation of three
serine/threonine residues in the M2-3 loop also reduced inactivation,
as did substitution of the intracellular C terminus of NR2A for NR2C.
We speculate that the M2-3 loop of NR2 modulates calcium-dependent
inactivation by interacting with the NR1 C terminus, a region known to
be essential for inactivation.
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