The role of post-translational modifications in synaptic AMPA receptor activity

AMPA-type receptors for the neurotransmitter glutamate are very dynamic entities, and changes in their synaptic abundance underlie different forms of synaptic plasticity, including long-term synaptic potentiation (LTP), long-term depression (LTD) and homeostatic scaling. The different AMPA receptor subunits (GluA1-GluA4) share a common modular structure and membrane topology, and their intracellular C-terminus tail is responsible for the interaction with intracellular proteins important in receptor trafficking. The latter sequence differs between subunits and contains most sites for post-translational modifications of the receptors, including phosphorylation, O-GlcNAcylation, ubiquitination, acetylation, palmitoylation and nitrosylation, which affect differentially the various subunits. Considering that each single subunit may undergo modifications in multiple sites, and that AMPA receptors may be formed by the assembly of different subunits, this creates multiple layers of regulation of the receptors with impact in synaptic function and plasticity. This review discusses the diversity of mechanisms involved in the post-translational modification of AMPA receptor subunits, and their impact on the subcellular distribution and synaptic activity of the receptors.