SRC3 acetylates calmodulin in the mouse brain to regulate synaptic plasticity and fear learning

Zhang, Hai-Long; Han, Wei; Du, Yin-Quan; Zhao, Bing; Yin, Dong-Min

doi:10.1016/j.jbc.2021.101044

Cited by 4 publications

(9 citation statements)

References 47 publications

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“…28 In previous studies, we demonstrated that SRC3-mediated CaM acetylation was important for CaMKIIα activity and hippocampus-dependent memory in mice. 31,45,46 Here, we showed that HDAC9-mediated CaM deacetylation and CaMKIIα activity are severely abnormal in AD mouse brain.…”

Section: Discussionmentioning

confidence: 77%

“…While total CaM, CaMKIIα, GluR1, and PSD95 did not change significantly in WT and APP/PS1 mice (Figure 2A,E–H,J,N–Q). In previous studies, we identified that SRC3 was the CaM acetyltransferase, and revealed that CaM acetylation was necessary for CaMKIIα activation 31,45,46 . We studied whether decreased CaM acetylation is caused by reduced SRC3, and found that SRC3 did not change significantly in APP/PS1 mice, compared to WT mice (Figure 2A,I,J,R).…”

Section: Resultsmentioning

confidence: 86%

“…In previous studies, we identified that SRC3 was the CaM acetyltransferase, and revealed that CaM acetylation was necessary for CaMKIIα activation. 31,45,46 We studied whether decreased CaM acetylation is caused by reduced SRC3, and found that SRC3…”

Section: Alteration Of Cam Acetylation In Ad Patients and Micementioning

confidence: 99%

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HDAC9‐mediated calmodulin deacetylation induces memory impairment in Alzheimer's disease

Zhang,

Hu,

Yang

et al. 2024

CNS Neurosci Ther

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AimsAlzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive dysfunction and memory impairment. AD pathology involves protein acetylation. Previous studies have mainly focused on histone acetylation in AD, however, the roles of nonhistone acetylation in AD are less explored.MethodsThe protein acetylation and expression levels were detected by western blotting and co‐immunoprecipitation. The stoichiometry of acetylation was measured by home‐made and site‐specific antibodies against acetylated‐CaM (Ac‐CaM) at K22, K95, and K116. Hippocampus‐dependent learning and memory were evaluated by using the Morris water maze, novel object recognition, and contextual fear conditioning tests.ResultsWe showed that calmodulin (CaM) acetylation is reduced in plasma of AD patients and mice. CaM acetylation and its target Ca2+/CaM‐dependent kinase II α (CaMKIIα) activity were severely impaired in AD mouse brain. The stoichiometry showed that Ac‐K22, K95‐CaM acetylation were decreased in AD patients and mice. Moreover, we screened and identified that lysine deacetylase 9 (HDAC9) was the main deacetylase for CaM. In addition, HDAC9 inhibition increased CaM acetylation and CaMKIIα activity, and hippocampus‐dependent memory in AD mice.ConclusionsHDAC9‐mediated CaM deacetylation induces memory impairment in AD, HDAC9, or CaM acetylation may become potential therapeutic targets for AD.

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Section: Discussionmentioning

confidence: 77%

Section: Resultsmentioning

confidence: 86%

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HDAC9‐mediated calmodulin deacetylation induces memory impairment in Alzheimer's disease

Zhang,

Hu,

Yang

et al. 2024

CNS Neurosci Ther

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“…In the central nervous system, activation of NMDA receptors on the postsynaptic membrane leads to an increase in the local concentration of postsynaptic Ca 2+ , which binds to and activates CaM. Activated CaM activates Ca 2+ /CaM-dependent CaMKII, which plays an important role in synaptic plasticity, learning, and memory ( Zhang et al, 2021 ). KN-93 is a CaMKII inhibitor, which reduces the expression level and activity of CaMKII, as well as the phosphorylation level of its phosphorylation site Thr 305 ( Munevar et al, 2008 ).…”

Section: Discussionmentioning

confidence: 99%

“…Many extracellular signals, such as neurotransmitters and hormones, regulate Ca 2+ content after interacting with receptors on cell membranes. Ca 2+ activates protein phosphatase and participates in synaptic plasticity regulation ( Roche et al, 1993 ; Zhang et al, 2021 ). As a result, we also investigated the mechanism, by which androgens affect synaptic protein PSD95 in HT22 cells through the Ca 2+ -induced Ca 2+ /CaMKII signaling pathway, and provided evidence for the neuroprotective effect of androgens.…”

Section: Introductionmentioning

confidence: 99%

CaMKII is a modulator in neurodegenerative diseases and mediates the effect of androgen on synaptic protein PSD95

Chen

Lin

et al. 2022

Front. Genet.

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Androgens rapidly regulate synaptic plasticity in hippocampal neurones, but the underlying mechanisms remain unclear. In this study, we carried out a comprehensive bioinformatics analysis of functional similarities between androgen receptor (AR) and the synaptic protein postsynaptic density 95 (PSD95) to evaluate the effect. Using different measurements and thresholds, we obtained consistent results illustrating that the two proteins were significantly involved in similar pathways. We further identified CaMKII plays a critical role in mediating the rapid effect of androgen and promoting the expression of PSD95. We used mouse hippocampal neurone HT22 cells as a cell model to investigate the effect of testosterone (T) on intracellular Ca2+ levels and the mechanism. Calcium imaging experiments showed that intracellular Ca2+ increased to a peak due to calcium influx in the extracellular fluid through L-type and N-type voltage-gated calcium channels when HT22 cells were treated with 100 nM T for 20 min. Subsequently, we investigated whether the Ca2+/CaMKII signaling pathway mediates the rapid effect of T, promoting the expression of the synaptic protein PSD95. Immunofluorescence cytochemical staining and western blotting results showed that T promoted CaMKII phosphorylation by rapidly increasing extracellular Ca2+ influx, thus increasing PSD95 expression. This study demonstrated that CaMKII acts as a mediator assisting androgen which regulates the synaptic protein PSD95Also, it provides evidence for the neuroprotective mechanisms of androgens in synaptic plasticity and reveals the gated and pharmacological mechanisms of the voltage-gated Ca2+ channel family for androgen replacement therapy.

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Dynamic regulation of NAT10-mediated mRNA acetylation at synapses by learning and memory in mouse hippocampus

Zhou,

Zhang,

Zhu

et al. 2024

Preprint

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N4-acetylcytidine (ac4C) is the only RNA acetylation modification identified in eukaryotes and has recently been recognized as an epitranscriptomic mechanism regulating mRNA stability and translation efficiency. However, the function and regulation of mRNA acetylation in the brain remain largely unknown. In this study, the presence of ac4C in mRNA was demonstrated by dot blot analysis and UPLC-MS/MS. A transcriptome-wide mapping of ac4C was performed in the hippocampus of adult mice trained in the Morris water maze, a protocol for learning and memory. Notably, the protein levels of N-acetyltransferase 10 (NAT10), the ac4C writer, increased at synapses following memory formation but returned to baseline levels after forgetting. Moreover, the downregulation of NAT10-mediated N4-acetylcytidine in mRNA in the mouse hippocampus using the Cre/LoxP strategy resulted in impaired synaptic plasticity and deficits in learning and memory. These findings underscore the dynamics and functions of synaptic mRNA acetylation during learning and memory, providing novel insights into the epitranscriptomic regulation of brain function. The ac4C epitranscriptome dataset in mouse hippocampus is accessible via the website (http://ac4Catlas.com/).

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SRC3 acetylates calmodulin in the mouse brain to regulate synaptic plasticity and fear learning

Cited by 4 publications

References 47 publications

HDAC9‐mediated calmodulin deacetylation induces memory impairment in Alzheimer's disease

HDAC9‐mediated calmodulin deacetylation induces memory impairment in Alzheimer's disease

CaMKII is a modulator in neurodegenerative diseases and mediates the effect of androgen on synaptic protein PSD95

Dynamic regulation of NAT10-mediated mRNA acetylation at synapses by learning and memory in mouse hippocampus

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