Abstract
A new N-methyl D aspartate neurotransmitter receptor interacting protein has been identified by yeast two-hybrid screening of a mouse brain cDNA library. C-terminal binding protein 1 (CtBP1) was shown to associate with the intracellular C-terminal regions of the N-methyl D aspartate receptor subunits GluN2A and GluN2D but not with GluN1-1a cytoplasmic C-terminal region. In yeast mating assays using a series of GluN2A C-terminal truncations, it was demonstrated that the CtBP1 binding domain was localized to GluN2A 1157–1382. The GluN2A binding domain was identified to lie within the CtBP1 161–224 region. CtBP1 co-immunoprecipitated with assembled GluN1/GluN2A receptors expressed in mammalian cells and also, in detergent extracts of adult mouse brain. Co-expression of CtBP1 with GluN1/GluN2A resulted in a significant decrease in receptor cell surface expression. The family of C-terminal binding proteins function primarily as transcriptional co-repressors. However, they are also known to modulate intracellular membrane trafficking mechanisms. Thus the results reported herein describe a putative role for CtBP1 in the regulation of cell surface N-methyl D aspartate receptor expression.
Highlights
Excitatory N-methyl-D-aspartate (NMDA) neurotransmitter receptors are key brain proteins because of the central role they play in long term potentiation and long term depression, mechanisms of learning and memory; in synaptogenesis during the development of the central nervous system, Special Issue: In honor of Prof
The C-terminal binding protein 1 (CtBP1) amino acid sequence that is common to both clones, i.e. CtBP1 161–224 is identical across all five CtBP1 variants (Fig. 2)
We have shown that CtBP1 co-immunoprecipitates with assembled GluN1/ GluN2A receptors and importantly, expression of CtBP1 with GluN1/GluN2A resulted in a decreased cell surface receptor expression
Summary
Excitatory N-methyl-D-aspartate (NMDA) neurotransmitter receptors are key brain proteins because of the central role they play in long term potentiation and long term depression, mechanisms of learning and memory; in synaptogenesis during the development of the central nervous system, Special Issue: In honor of Prof. The membrane associated guanylate kinase (MAGUK) family of scaffolding proteins are key components linking NMDA receptors with intracellular signalling pathways. They bind via their PDZ1 and PDZ domains to a motif, ES(D/E)V that is common to all GluN2 subunit C-termini. Several reports have suggested that GluN2D-containing receptors are extra-synaptic [9,10,11,12] This together with the findings that GluN2D-containing receptors interacted differently with the MAGUK proteins [5, 6] and the fact that the GluN2D intracellular C-terminal tail contains multiple protein–protein interaction domains (Fig. 1), led to a yeast-two hybrid screen conducted with the aim to identify a GluN2D targeting protein.
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