Glutamate binding to the GluN2B subunit controls surface trafficking of N-methyl-D-aspartate (NMDA) receptors.
J. Biol. Chem.. 2012-06-27; 287(33): 27432-27445
Lire sur PubMed
1. J Biol Chem. 2012 Aug 10;287(33):27432-45. doi: 10.1074/jbc.M112.345108. Epub
2012 Jun 27.
Glutamate binding to the GluN2B subunit controls surface trafficking of
N-methyl-D-aspartate (NMDA) receptors.
She K(1), Ferreira JS, Carvalho AL, Craig AM.
(1)Brain Research Centre and Department of Psychiatry, University of British
Columbia, Vancouver, British Columbia V6T 2B5, Canada.
Trafficking of NMDA receptors to the surface of neurons and to synapses is
critical for proper brain function and activity-dependent plasticity. Recent
evidence suggests that surface trafficking of other ionotropic glutamate
receptors requires ligand binding for exit from the endoplasmic reticulum. Here,
we show that glutamate binding to GluN2 is required for trafficking of NMDA
receptors to the cell surface. We expressed a panel of GluN2B ligand binding
mutants in heterologous cells with GluN1 or in rat cultured neurons and found
that surface expression correlates with glutamate efficacy. Such a correlation
was found even in the presence of dominant negative dynamin to inhibit
endocytosis and surface expression correlated with Golgi localization, indicating
differences in forward trafficking. Co-expression of wild type GluN2B did not
enhance surface expression of the mutants, suggesting that glutamate must bind to
both GluN2 subunits in a tetramer and that surface expression is limited by the
least avid of the two glutamate binding sites. Surface trafficking of a
constitutively closed cleft GluN2B was indistinguishable from that of wild type,
suggesting that glutamate concentrations are typically not limiting for forward
trafficking. YFP-GluN2B expressed in hippocampal neurons from GluN2B(-/-) mice
rescued synaptic accumulation at similar levels to wild type. Under these
conditions, surface synaptic accumulation of YFP-GluN2B mutants also correlated
with apparent glutamate affinity. Altogether, these results indicate that
glutamate controls forward trafficking of NMDA receptors to the cell surface and
to synapses and raise the intriguing idea that NMDA receptors may be functional
at intracellular sites.
PMID: 22740692 [Indexed for MEDLINE]