Key Laboratory of Brain Functional Genomics, Ministry of Education and Shanghai, School of Life Science, East China Normal University, Shanghai, China; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China.
Key Laboratory of Brain Functional Genomics, Ministry of Education and Shanghai, School of Life Science, East China Normal University, Shanghai, China.
J Biol Chem. 2021 Sep;297(3):101034. doi: 10.1016/j.jbc.2021.101034. Epub 2021 Jul 31.
Synaptic plasticity is critical for brain function, including learning and memory. It is regulated by gene transcription and protein synthesis as well as posttranslational modifications at synapses. Although protein acetylation has been shown to be involved in the regulation of synaptic plasticity, this was mainly for histone protein acetylation. To investigate whether acetylation of nonhistone proteins is important for synaptic plasticity, we analyzed mouse brain acetylome and found that calmodulin (CaM), a ubiquitous Ca sensor, was acetylated on three lysine residues, which were conserved across species. NMDA receptor-dependent long-term potentiation (LTP) is considered the most compelling form of synaptic plasticity. During LTP induction, activation of NMDA receptor triggers Ca influx, and the Ca binds with CaM and activates calcium/calmodulin-dependent protein kinase IIα (CaMKIIα), which is essential for LTP induction. By using home-generated and site-specific antibodies against acetylated CaM, we show that CaM acetylation is upregulated by neural activities in an NMDA receptor-dependent manner. Moreover, mutation of acetyllysines in CaM1 proteins disrupts synaptic plasticity and fear learning in a mouse model. We further demonstrate that acetylation of CaM reduces the binding free energy and increases the binding affinity toward CaMKIIα, a protein kinase pivotal to synaptic plasticity and learning. Taken together, our results demonstrate importance of CaM acetylation in regulating synaptic plasticity and learning.
突触可塑性对于大脑功能至关重要，包括学习和记忆。它受到基因转录和蛋白质合成以及突触后翻译后修饰的调节。尽管已经表明蛋白质乙酰化参与了突触可塑性的调节，但这主要是针对组蛋白蛋白乙酰化。为了研究非组蛋白蛋白的乙酰化是否对突触可塑性很重要，我们分析了小鼠大脑乙酰组并发现钙调蛋白（CaM），一种普遍存在的 Ca 传感器，在三个赖氨酸残基上被乙酰化，这些赖氨酸残基在物种间是保守的。NMDA 受体依赖性长时程增强（LTP）被认为是最具说服力的突触可塑性形式。在 LTP 诱导期间，NMDA 受体的激活触发 Ca 内流，Ca 与 CaM 结合并激活钙/钙调蛋白依赖性蛋白激酶 IIα（CaMKIIα），这对于 LTP 诱导至关重要。通过使用针对乙酰化 CaM 的自制和特异性抗体，我们表明 CaM 乙酰化通过 NMDA 受体依赖性方式被神经活动上调。此外，CaM1 蛋白中乙酰赖氨酸的突变会破坏突触可塑性和恐惧学习在小鼠模型中。我们进一步证明 CaM 的乙酰化降低了与 CaMKIIα的结合自由能并增加了结合亲和力，CaMKIIα是对突触可塑性和学习至关重要的蛋白激酶。总之，我们的结果表明 CaM 乙酰化在调节突触可塑性和学习中的重要性。
