Crucial Roles for SIRT2 and AMPA Receptor Acetylation in Synaptic Plasticity and Memory

Abstract

SUMMARY AMPA receptors (AMPARs) mediate fast excitatory synaptic transmission and are crucial for synaptic plasticity, learning and memory. However, the molecular control of AMPAR stability and its neurophysiological significance remain unclear. Here we report that AMPARs are subject to lysine acetylation at their C-termini. Acetylation reduces AMPAR internalization and degradation, leading to increased cell-surface localization and prolonged receptor half-life. Through competition for the same lysine residues, acetylation intensity is inversely related to the levels of AMPAR ubiquitination. We find that sirtuin 2 (SIRT2) acts as an AMPAR deacetylase regulating AMPAR trafficking and proteostasis. SIRT2 knockout mice (Sirt2−/−) show marked up-regulation in AMPAR acetylation and protein accumulation. Both Sirt2−/− mice and mice expressing acetylation mimetic GluA1 show aberrant synaptic plasticity, accompanied with impaired learning and memory. These findings establish SIRT2-regulated lysine acetylation as a form of AMPAR post-translational modification that regulates its turnover, as well as synaptic plasticity and cognitive function.

Memory Synapses Are Defined by Distinct Molecular Complexes: A Proposal

“…There are at least five sources of diversity in AMPA receptor complexes: (1) Separate genes encode distinct isoforms of AMPA receptors (there are four AMPA receptors in vertebrates, GluA1-4); (2) Post-transcriptional modifications of these receptors, including alternative splicing (Penn and Greger, 2009 ) and RNA editing (Hood and Emeson, 2012 ) which can generate many different forms of the proteins even from the same transcribed mRNA (Greger et al, 2017 ); (3) The tetrameric structure of the receptors allows multiple combinations of distinct genes and post-transcriptionally modified genes to combine, increasing the complexity of a single tetrameric receptor (Henley and Wilkinson, 2016 ); (4) Post-translational modifications such as phosphorylation (Lu and Roche, 2012 ; Wang et al, 2014 ), ubiquitination (Goo et al, 2015 ), acetylation (Wang et al, 2017 ), and palmitoylation (Han et al, 2015 ) alter the function of the receptors; and (5) Distinct associated proteins make up distinct AMPA receptor complexes, such as TARPS, Cornichons, and others (Schwenk et al, 2012 ). Since a large amount of synaptic plasticity rests on transferring AMPA receptors in and out of the postsynaptic density, it does not take much imagination to see that depending on the composition of these AMPA receptor complexes, the regulation of their insertion and removal at synapses will be different.…”

The Clinical Significance of SIRT2 in Malignancies: A Tumor Suppressor or an Oncogene?

“…Last decade, many new substrates and SIRT2-related proteins had been identified, such as CDK9, PGAM2, Par-3, and CDH1/CDC20, etc. ( Table 1) (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). These results suggest that SIRT2 regulates multiple biological functions, including neurotoxicity, metabolism, mitosis regulation, genome integrity, oxidative stress, and autophagy ( Table 1).…”

It is a complex issue: emerging connections between epigenetic regulators in drug addiction

“…For example, the HAT p300/CBP (CREBbinding protein) acetylates various transcription activators, including the transcription factors, p53, Myogenic Differentiation 1 (MyoD), GATA Binding Protein 1 (GATA-1), and Transcription Factor II E beta (Marmorstein, 2001), which alters their functions or stability. Similarly, the HDAC, sirtuin (SIRT) 2, can alter neuronal function by regulating acetylation state of the C-terminal tail of the ionotropic glutamate receptor A1 (GluA1), which highlights the fact that HATs/HDACs influence cell function independent of their chromatin-remodeling capabilities (Wang et al, 2017). Interestingly, HDACs themselves can be acetylated, which can influence their enzymatic activity.…”