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学术讲座——Regulation of AMPA receptor acetylation and translation by sirt2 and AMPK: the molecular mechanisms and implications in memory formation

 

转化系统生物学与神经科学系列讲座(十五)

题目:Regulation of AMPA receptor acetylation and translation by sirt2 and AMPK: the molecular mechanisms and implications in memory formation

时间:2016617日上午10:20-12:00

地点:唐仲英科技楼三楼324报告厅

主讲专家:Wang GuanPhD(美国哥伦比亚大学)

主持人:陈刚教授

AbstractThe α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are ligand-gated glutamatergic ion channels that mediate most excitatory neurotransmission in the brain. However, the molecular mechanisms regulating AMPAR expression and dynamics in neurons remain largely unknown. It is shown that SIRT2, a NAD+-dependent protein deacetylase, directly controls AMPAR stability by regulating AMPAR acetylation. For the first time, we discovered that AMPARs are subject to lysine acetylation, a novel form of post-translational modification for glutamate receptors. Under basal conditions, AMPARs are highly acetylated at their intracellular C termini, which protects against ubiquitination to antagonize AMPAR endocytosis and degradation, leading to prolonged receptor half-life. SIRT2 is also identified as the enzyme responsible for AMPAR deacetylation. Knockdown of SIRT2 led to elevated AMPAR acetylation and reduced ubiquitination, and consequently, increased AMPAR levels and synaptic transmission. SIRT2 knockout mice displayed weakened synaptic plasticity and impaired learning and memory.

Resveratrol is a phytoalexin that has been shown to increase AMPAR expression and synaptic accumulation in neurons. Application of the AMPK activator, 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR),to neurons mimics the effects of resveratrol on both signaling and AMPAR expression. The resveratrol-induced increase in AMPAR expression results from elevated protein synthesis through the AMPK-PI3K pathway activation. These studies describe novel regulatory mechanisms responsible for the control of AMPAR protein amount and subcellular distribution in neurons, providing insights into our understanding of synaptic plasticity, brain function and neurological disorders.

 

附件:GUAN WANG_CV_2016

中医脑病学重点实验室

基础医学院    

2016年6月12日  

 

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