CaMKII phosphorylation of neuroligin-1 regulates excitatory synapses

Bemben, Michael A.; Shipman, Seth L.; Hirai, Takanori; Herring, Bruce E.; Li, Yan; Badger, John D.; Nicoll, Roger A.; Diamond, Jeffrey S.; Roche, Katherine W.

doi:10.1038/nn.3601

Cited by 92 publications

(99 citation statements)

References 50 publications

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“…Before this report, the importance of protein phosphorylation on NLGN1 was established (15,16). CaMKII phosphorylation of T739 regulates NLGN1's ability to potentiate excitatory synaptic transmission by regulating its surface expression.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, two autism-associated mutations in NLGN3 (R451C) and NLGN4X (R87W) were shown to disrupt surface expression (18,19). Moreover, phosphorylation of the NLGN1 c-tail regulates its forward trafficking (16). Does T707 regulate NLGN4X surface expression?…”

Section: Significancementioning

confidence: 99%

“…Protein phosphorylation is a critical modulator of NLGN function (15,16). Recently, we showed that Ca 2+ /CaM kinase II (CaMKII) phosphorylates the c-tail of NLGN1 in an isoform-specific and activity-dependent manner, which regulates its ability to enhance excitatory synapses (16).…”

mentioning

confidence: 99%

“…Recently, we showed that Ca 2+ /CaM kinase II (CaMKII) phosphorylates the c-tail of NLGN1 in an isoform-specific and activity-dependent manner, which regulates its ability to enhance excitatory synapses (16). Next, we wondered if different kinases might regulate the function of other NLGN isoforms?…”

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confidence: 99%

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Autism-associated mutation inhibits protein kinase C-mediated neuroligin-4X enhancement of excitatory synapses

Bemben

Nguyen

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Autism spectrum disorders (ASDs) comprise a highly heritable, multifarious group of neurodevelopmental disorders, which are characterized by repetitive behaviors and impairments in social interactions. Point mutations have been identified in X-linked Neuroligin (NLGN) 3 and 4X genes in patients with ASDs and all of these reside in their extracellular domains except for a single point mutation in the cytoplasmic domain of NLGN4X in which an arginine is mutated to a cysteine (R704C). Here we show that endogenous NLGN4X is robustly phosphorylated by protein kinase C (PKC) at T707, and R704C completely eliminates T707 phosphorylation. Endogenous NLGN4X is intensely phosphorylated on T707 upon PKC stimulation in human neurons. Furthermore, a phosphomimetic mutation at T707 has a profound effect on NLGN4X-mediated excitatory potentiation. Our results now establish an important interplay between a genetic mutation, a key posttranslational modification, and robust synaptic changes, which can provide insights into the synaptic dysfunction of ASDs.n a 2014 report published by the Centers for Disease Control and Prevention (CDC), it was estimated that 1 in 68 children in the United States have an autism spectrum disorder (ASD) (1). These neuropsychiatric disorders have a strong genetic component consistent with high recurrence rates between siblings and a higher concordance frequency seen in monozygotic than dizygotic twins. Furthermore, deletions, insertions, and substitutions have been identified within the genome that increase the risk of these disorders (2, 3). These cytogenetic and genome sequencing studies have revealed that Neuroligins (NLGNs) are one of a subset of genes encoding synaptic proteins associated with ASDs (4, 5).The NLGN gene family consists of five members (Nlgn1, 2, 3, 4X, and 4Y) within the human genome that encode transsynaptic cell adhesion molecules that are critical for synapse assembly, maintenance, and plasticity (5-7). Numerous studies have identified a variety of mutations in X-linked NLGN3 and 4X genes that range from copy number variants (8-11) to protein truncations and amino acid substitutions in patients with ASDs (4,12,13). Interestingly, all of the point mutations in NLGN3 and NLGN4X reside in their extracellular domains except for a single point mutation in the cytoplasmic domain (c-tail) of NLGN4X at arginine (R) 704, which is modified to a cysteine (C) (14). How this mutation or other NLGN disease mutations contribute to the pathophysiology is unknown.Protein phosphorylation is a critical modulator of NLGN function (15, 16). Recently, we showed that Ca 2+ /CaM kinase II (CaMKII) phosphorylates the c-tail of NLGN1 in an isoform-specific and activity-dependent manner, which regulates its ability to enhance excitatory synapses (16). Next, we wondered if different kinases might regulate the function of other NLGN isoforms?In the present study, we show in vitro and in vivo that NLGN4X is robustly phosphorylated by protein kinase C (PKC).We identified the dominant phosphorylation site as...

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Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Autism-associated mutation inhibits protein kinase C-mediated neuroligin-4X enhancement of excitatory synapses

Bemben

Nguyen

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…It is possible that association of cytosolic PDZ binding proteins, like CRIPT, triggers oligomerization of PSD95 by dissociating PDZ3 from SH3-GK (14). Based on the current study, the alternative way of cross-linking PDZ3 and GK of PSD95 is worth considering: for example, postsynaptic neuroligin1, which forms a transsynaptic complex with neurexin and is the best ligand for the PDZ3 (17), is phosphorylated upstream of the PDZ binding motif (18) and is possibly capable of inducing the cross-linking. Through subsequent oligomerization, a single PSD95 could simultaneously cluster neurotransmitter receptors and neuroligin1, while allowing the association of additional cytosolic PDZ binding proteins.…”

mentioning

confidence: 86%

MAGUKs end a tale of promiscuity

Reißner

Missler

2014

Proc. Natl. Acad. Sci. U.S.A.

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Neuroligin 1 Regulates Autistic‐Like Repetitive Behavior through Modulating the Activity of Striatal D2 Receptor‐Expressing Medium Spiny Neurons

Lv,

Liu,

et al. 2024

Advanced Science

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Restricted and repetitive behavior (RRB) is a primary symptom of autism spectrum disorder (ASD), which poses a significant risk to individuals' health and is becoming increasingly prevalent. However, the specific cellular and neural circuit mechanisms underlying the generation of RRB remain unclear. In this study, it is reported that the absence of the ASD‐related protein Neuroligin 1 (NLGN1) in dopamine receptor D2‐expressing medium spiny neurons (D2‐MSNs) in the dorsal striatum is associated with the duration and frequency of self‐grooming and digging behaviors. The Nlgn1‐deficient D2‐MSNs are hyperactivated, which correlates with excessive self‐grooming and digging behaviors. Inhibiting the activity of D2‐MSNs reduces the duration and frequency of these RRBs. Furthermore, it is demonstrated that the generation of self‐grooming and digging behaviors depends on distinct patterns of D2‐MSN activity. Finally, through single‐nucleus RNA sequencing (sn‐RNAseq) and protein detection verification, it is revealed that the overactivation of protein kinase C (PKC) in Nlgn1‐deficient mice contributes to excessive repetitive behaviors and increased neuronal excitability. In this study, potential mechanisms are proposed for the generation of self‐grooming and digging behaviors, as well as suggest possible treatments and interventions ASD.

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CaMKII phosphorylation of neuroligin-1 regulates excitatory synapses

Cited by 92 publications

References 50 publications

Autism-associated mutation inhibits protein kinase C-mediated neuroligin-4X enhancement of excitatory synapses

Autism-associated mutation inhibits protein kinase C-mediated neuroligin-4X enhancement of excitatory synapses

MAGUKs end a tale of promiscuity

Neuroligin 1 Regulates Autistic‐Like Repetitive Behavior through Modulating the Activity of Striatal D2 Receptor‐Expressing Medium Spiny Neurons

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