Regulation of NMDA receptor trafficking and gating by activity-dependent CaMKIIα phosphorylation of the GluN2A subunit

Yong, Xuan Ling Hilary; Zhang, Lingrui; Yang, Liming; Chen, Xiumin; Tan, Jing Zhi Anson; Yu, Xiaojun; Chandra, Mintu; Livingstone, Emma; Widagdo, Jocelyn; Vieira, Marta; Roche, Katherine W.; Lynch, Joseph W.; Keramidas, Angelo; Collins, Brett; Anggono, Victor

doi:10.1016/j.celrep.2021.109338

Cited by 23 publications

(15 citation statements)

References 68 publications

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“…CaMKII was one of the PSD members in excitatory synapses, regulating NMDA-receptor-dependent synaptic potentiation. NMDA-receptor-mediated EPSCs mediate calcium flux into the postsynaptic compartment, primarily activating downstream CaMKII, resulting in autophosphorylation of the kinase, leading to induction and maintenance of synaptic potentiation that are crucial for neuronal development, synaptic and structural plasticity, learning, and memory ( Lisman, 2017 ; Yong et al, 2021 ). Recently, a gene mutant mouse study identified that αCaMKII autophosphorylation-dependent remodeling of glutamatergic synapses is a plausible mechanism for behavior related to alcohol addiction ( Mijakowska et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Proteomics and weighted gene correlated network analysis reveal glutamatergic synapse signaling in diazepam treatment of alcohol withdrawal

Kong

Huang²,

Chen³

et al. 2023

Front. Pharmacol.

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Background: Alcohol use disorder (AUD) is characterized by chronic excessive alcohol consumption, often alternating with periods of abstinence known as alcohol withdrawal syndrome (AWS). Diazepam is the preferred benzodiazepine for treatment of alcohol withdrawal syndrome under most circumstances, but the specific mechanism underlying the treatment needs further research.Methods: We constructed an animal model of two-bottle choices and chronic intermittent ethanol exposure. LC-MS/MS proteomic analysis based on the label-free and intensity-based quantification approach was used to detect the protein profile of the whole brain. Weighted gene correlated network analysis was applied for scale-free network topology analysis. We established a protein–protein interaction network based on the Search Tool for the Retrieval of Interacting Genes (STRING) database and Cytoscape software and identified hub proteins by CytoHubba and MCODE plugins of Cytoscape. The online tool Targetscan identified miRNA–mRNA pair interactions.Results: Seven hub proteins (Dlg3, Dlg4, Shank3, Grin2b, Camk2b, Camk2a and Syngap1) were implicated in alcohol withdrawal syndrome or diazepam treatment. In enrichment analysis, glutamatergic synapses were considered the most important pathway related to alcohol use disorder. Decreased glutamatergic synapses were observed in the late stage of withdrawal, as a protective mechanism that attenuated withdrawal-induced excitotoxicity. Diazepam treatment during withdrawal increased glutamatergic synapses, alleviating withdrawal-induced synapse inhibition.Conclusion: Glutamatergic synapses are considered the most important pathway related to alcohol use disorder that may be a potential molecular target for new interventional strategies.

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Section: Discussionmentioning

confidence: 99%

Proteomics and weighted gene correlated network analysis reveal glutamatergic synapse signaling in diazepam treatment of alcohol withdrawal

Kong

Huang²,

Chen³

et al. 2023

Front. Pharmacol.

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“…In further support of a prominent role of microglial TNFα at synapses during sleep, several known functional phosphosites on pre- and postsynaptic proteins were identified as regulated by TNFα during sleep (fig.4 and table S2). For instance, the postsynaptic NMDAR 2A subunit (Grin2a) display changes in the phosphorylations of Ser 929 and Ser 1459 , residues involved in the trafficking and synaptic presentation of the receptor ( 79 , 80 ), whilst NMDAR 2B subunit (Grin2b) becomes dephosphorylated at Ser 1303 known to control its binding to CaMKII ( 81 ). The latter is a central kinase in postsynaptic plasticity whose activity is controlled by phosphorylation at Thr 286 ( 37 ), also shown to be modified by TNFα.…”

Section: Discussionmentioning

confidence: 99%

Microglial TNFα orchestrates brain phosphorylation during the sleep period and controls homeostatic sleep

Pinto

Cottin

Dingli

et al. 2022

Preprint

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The time we spend asleep is adjusted to previous time spent awake, and therefore believed to be under tight homeostatic control. Here, we establish microglia as a new cellular component of the sleep homeostat circuit. By using quantitative phosphoproteomics we demonstrate that microglia-derived TNFα controls thousands of phosphorylation sites during the sleep period. Substrates of microglial TNFα comprise sleep-promoting kinases and numerous synaptic proteins, including a subset whose phosphorylation status codes sleep need and determines sleep duration. As a result, lack of microglial TNFα attenuates the build-up of sleep need, as measured by slow wave activity, and prevents immediate compensation for loss of sleep. Together, we propose that microglia control sleep homeostasis by releasing TNFα that acts at the neuronal circuitry through dynamic control of phosphorylation. attenuates the build-up of sleep need, as measured by slow wave activity, and prevents immediate compensation for loss of sleep. Together, we propose that microglia control sleep homeostasis by releasing TNFα that acts at the neuronal circuitry through dynamic control of phosphorylation.

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“…Interestingly, while the above study shows that the CTD of GluN2A can be swapped for that of GluN2B with no impairment of GluN2A surface expression, recent studies suggested that in the context of the CTD 2A , certain residues may be functionally important for surface expression of GluN2A. Work by Mota Vieira et al [ 21 ] and Yong et al [ 22 ] aimed to functionally characterise the epilepsy- associated variant GluN2A-S1459G and identified S1459 as a CaMKIIα phosphorylation site controlled in a development and activity-dependent manner whose mutation impaired interactions with SNX27 and PSD95 as well as GluN2A surface expression when ectopically expressed in cultured neurons. Generation and characterisation of a GluN2A-S1459G KI mouse would further strengthen the case for this phosphorylation event being functionally important for activity-dependent and/or developmental surface expression of GluN2A.…”

Section: The Role Of the Ctd In Developmental And Activity-dependent ...mentioning

confidence: 91%

NMDA Receptor C-Terminal Domain Signalling in Development, Maturity, and Disease

Haddow

Kind

Hardingham

2022

IJMS

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The NMDA receptor is a Ca2+-permeant glutamate receptor which plays key roles in health and disease. Canonical NMDARs contain two GluN2 subunits, of which 2A and 2B are predominant in the forebrain. Moreover, the relative contribution of 2A vs. 2B is controlled both developmentally and in an activity-dependent manner. The GluN2 subtype influences the biophysical properties of the receptor through difference in their N-terminal extracellular domain and transmembrane regions, but they also have large cytoplasmic Carboxyl (C)-terminal domains (CTDs) which have diverged substantially during evolution. While the CTD identity does not influence NMDAR subunit specific channel properties, it determines the nature of CTD-associated signalling molecules and has been implicated in mediating the control of subunit composition (2A vs. 2B) at the synapse. Historically, much of the research into the differential function of GluN2 CTDs has been conducted in vitro by over-expressing mutant subunits, but more recently, the generation of knock-in (KI) mouse models have allowed CTD function to be probed in vivo and in ex vivo systems without heterologous expression of GluN2 mutants. In some instances, findings involving KI mice have been in disagreement with models that were proposed based on earlier approaches. This review will examine the current research with the aim of addressing these controversies and how methodology may contribute to differences between studies. We will also discuss the outstanding questions regarding the role of GluN2 CTD sequences in regulating NMDAR subunit composition, as well as their relevance to neurodegenerative disease and neurodevelopmental disorders.

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Regulation of NMDA receptor trafficking and gating by activity-dependent CaMKIIα phosphorylation of the GluN2A subunit

Cited by 23 publications

References 68 publications

Proteomics and weighted gene correlated network analysis reveal glutamatergic synapse signaling in diazepam treatment of alcohol withdrawal

Proteomics and weighted gene correlated network analysis reveal glutamatergic synapse signaling in diazepam treatment of alcohol withdrawal

Microglial TNFα orchestrates brain phosphorylation during the sleep period and controls homeostatic sleep

NMDA Receptor C-Terminal Domain Signalling in Development, Maturity, and Disease

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