Abstract
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 upregulation in AMPAR acetylation and protein accumulation. Both Sirt2−/− mice and mice expressing acetylation mimetic GluA1 show aberrant synaptic plasticity, accompanied by 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.
Original language | English (US) |
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Pages (from-to) | 1335-1347 |
Number of pages | 13 |
Journal | Cell Reports |
Volume | 20 |
Issue number | 6 |
DOIs | |
State | Published - Aug 8 2017 |
Externally published | Yes |
Keywords
- acetylation
- AMPA receptors
- AMPARs
- cognitive function
- deacetylase
- learning and memory
- receptor trafficking
- sirtuin 2
- synaptic plasticity
- ubiquitination
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology