Dynamic Regulation of N-Methyl-d-aspartate (NMDA) and α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors by Posttranslational Modifications - PubMed (original) (raw)

Review

Dynamic Regulation of N-Methyl-d-aspartate (NMDA) and α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors by Posttranslational Modifications

Marc P Lussier et al. J Biol Chem. 2015.

Abstract

Many molecular mechanisms underlie the changes in synaptic glutamate receptor content that are required by neuronal networks to generate cellular correlates of learning and memory. During the last decade, posttranslational modifications have emerged as critical regulators of synaptic transmission and plasticity. Notably, phosphorylation, ubiquitination, and palmitoylation control the stability, trafficking, and synaptic expression of glutamate receptors in the central nervous system. In the current review, we will summarize some of the progress made by the neuroscience community regarding our understanding of phosphorylation, ubiquitination, and palmitoylation of the NMDA and AMPA subtypes of glutamate receptors.

Keywords: N-methyl-D-aspartate receptor (NMDA receptor, NMDAR); alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor, AMPAR); glutamate receptor; post-translational modification (PTM); protein palmitoylation; ubiquitin.

© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

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Figures

FIGURE 1.

FIGURE 1.

Cellular mechanisms regulating synaptic expression of GluRs. The synaptic molecular content of iGluRs is controlled by multiple cellular events.

FIGURE 2.

FIGURE 2.

PTMs decorate GluN2A and GluN2B C-terminal tails. The GluN2A and GluN2B C termini contain several amino acids (aa) modified by phosphorylation (serine (S) or tyrosine (Y)), ubiquitination (lysine K)), and palmitoylation (cysteine (C)). Kinases targeting a specific residue are illustrated.

FIGURE 3.

FIGURE 3.

PTMs modify AMPAR intracellular domains. The AMPAR C termini are substrates for several kinases targeting serine (S), threonine (T), or tyrosine (Y). Also, AMPARs are modified by palmitoylation on cysteines (C) and ubiquitination (UB) on lysines (K). The amino acids (aa) targeted by specific PTMs are depicted.

FIGURE 4.

FIGURE 4.

NMDAR lateral diffusion and endocytosis. GluN2B/2B receptor removal from synapses is controlled by the coordinated work of several kinases, including CaMKII, CK2, and Fyn/Src. In addition, PKC and Cdk5 may be involved in the process. The synaptic activity-dependent activation of CaMKII promotes phosphorylation on the PDZ ligand of GluN2B by CK2. This phosphorylation disrupts the interaction of the receptor with scaffolding proteins and leads to GluN2B internalization via dephosphorylation of the YEKL endocytic motif. See text for details.

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