Activity and protein kinase C regulate synaptic accumulation of N-methyl-D-aspartate (NMDA) receptors independently of GluN1 splice variant.
J. Biol. Chem.. 2011-06-15; 286(32): 28331-28342
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1. J Biol Chem. 2011 Aug 12;286(32):28331-42. doi: 10.1074/jbc.M111.222539. Epub
2011 Jun 15.
Activity and protein kinase C regulate synaptic accumulation of
N-methyl-D-aspartate (NMDA) receptors independently of GluN1 splice variant.
Ferreira JS(1), Rooyakkers A, She K, Ribeiro L, Carvalho AL, Craig AM.
(1)Center for Neuroscience and Cell Biology and Department of Life Sciences,
University of Coimbra, 3004-517 Coimbra, Portugal.
NMDA receptors are calcium-permeable ionotropic receptors that detect coincident
glutamate binding and membrane depolarization and are essential for many forms of
synaptic plasticity in the mammalian brain. The obligatory GluN1 subunit of NMDA
receptors is alternatively spliced at multiple sites, generating forms that vary
in N-terminal N1 and C-terminal C1, C2, and C2′ cassettes. Based on expression of
GluN1 constructs in heterologous cells and in wild type neurons, the prevalent
view is that the C-terminal cassettes regulate synaptic accumulation and its
modulation by homeostatic activity blockade and by protein kinase C (PKC). Here,
we tested the role of GluN1 splicing in regulated synaptic accumulation of NMDA
receptors by lentiviral expression of individual GluN1 splice variants in
hippocampal neurons cultured from GluN1 (-/-) mice. High efficiency transduction
of GluN1 at levels similar to endogenous was achieved. Under control conditions,
the C2′ cassette mediated enhanced synaptic accumulation relative to the
alternate C2 cassette, whereas the presence or absence of N1 or C1 had no effect.
Surprisingly all GluN1 splice variants showed >2-fold increased synaptic
accumulation with chronic blockade of NMDA receptor activity. Furthermore, in
this neuronal rescue system, all GluN1 splice variants were equally rapidly
dispersed upon activation of PKC. These results indicate that the major
mechanisms mediating homeostatic synaptic accumulation and PKC dispersal of NMDA
receptors occur independently of GluN1 splice isoform.
PMID: 21676872 [Indexed for MEDLINE]