Posttranslational modifications of neuroligins regulate neuronal and glial signaling

Jeong, Jong Ju; Paskus, Jeremiah D.; Roche, Katherine W.

doi:10.1016/j.conb.2017.05.017

Cited by 32 publications

(28 citation statements)

References 53 publications

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“…days to weeks, due to slow protein turnover. Hence, there is a pressing need for alternative paradigms allowing for an acute control of Nlg signaling pathways (Jeong et al, 2017) without affecting its expression level. Optogenetics is ideally suited for such purpose and was successfully implemented not only to regulate neuronal excitability and homeostasis, but also for fine tuning protein-protein interactions and signaling pathways in neurons with light (Berlin et al, 2016;Berlin and Isacoff, 2017;Chang et al, 2014;Goold and Nicoll, 2010;Grubb and Burrone, 2010;Mao et al, 2018;Schwechter et al, 2013;Sinnen et al, 2017;Zhang et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Optogenetic control of excitatory post-synaptic differentiation through neuroligin-1 tyrosine phosphorylation

Letellier

Lagardère

Tessier

et al. 2019

Preprint

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AbstractNeuroligins (Nlgs) are adhesion proteins mediating trans-synaptic contacts in neurons. However, conflicting results around their role in synaptic differentiation arise from the various techniques used to manipulate Nlg expression. Orthogonally to these approaches, we triggered here the phosphorylation of endogenous Nlg1 in CA1 hippocampal neurons using a photoactivatable tyrosine kinase receptor (optoFGFR1). Light stimulation for 24 h selectively increased dendritic spine density and AMPA receptor-mediated EPSCs in wild-type neurons, but not in Nlg1 knock-out neurons or when endogenous Nlg1 was replaced by a non-phosphorylatable mutant (Y782F). Moreover, light stimulation of optoFGFR1 partially occluded LTP. Combined with computer simulations, our data support a model by which Nlg1 tyrosine phosphorylation promotes the assembly of an excitatory post-synaptic scaffold that captures surface AMPA receptors. This optogenetic strategy thus highlights the impact of Nlg1 intracellular signaling in synaptic differentiation and potentiation, while enabling an acute control of these mechanisms.Impact StatementOrthogonal to the traditional paradigms used to manipulate neuroligin expression level, the optogenetic trigger of tyrosine phosphorylation supports a strong role of endogenous neuroligin-1 in excitatory synaptic differentiation and potentiation.

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Section: Introductionmentioning

confidence: 99%

Optogenetic control of excitatory post-synaptic differentiation through neuroligin-1 tyrosine phosphorylation

Letellier

Lagardère

Tessier

et al. 2019

Preprint

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“…In fact, all identified NLGN isoforms show high similarity in amino acid sequence. In addition, the defined protein binding domains in the cytoplasmic region, including the PDZ ligand, are well conserved in all NLGN isoforms (11,12). However, isoform-specific mechanisms regulating synaptic localization are not fully understood.Because NLGN1 and PSD-95 are both localized to excitatory synapses, and their direct interaction via third PDZ domain of PSD-95 was identified in an early study (13), PSD-95 and NLGN1 have been investigated together in many studies for their physiological roles in the glutamatergic signaling pathway.…”

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confidence: 99%

“…Meanwhile, synaptic targeting of NLGN1 is known to be independent of PSD-95, as PSD-95 is recruited to the plasma membrane after NLGN1 (13,16,17). In addition, non-PDZ ligand-dependent NLGN1 and NLGN3 functions have been investigated (18), suggesting a complicated physiological interplay between NLGNs and PSD-95.Posttranslational modifications have been reported for several NLGN isoforms and are postulated to confer distinct properties (11,12). For example, phosphorylation of the cytoplasmic region of NLGN1 has recently emerged as a mechanism for isoform-specific function (19,20).…”

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confidence: 99%

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confidence: 99%

“…Posttranslational modifications have been reported for several NLGN isoforms and are postulated to confer distinct properties (11,12). For example, phosphorylation of the cytoplasmic region of NLGN1 has recently emerged as a mechanism for isoform-specific function (19,20).…”

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PSD-95 binding dynamically regulates NLGN1 trafficking and function

Jeong

Pandey

et al. 2019

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

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PSD-95 is a scaffolding protein that regulates the synaptic localization of many receptors, channels, and signaling proteins. The NLGN gene family encodes single-pass transmembrane postsynaptic cell adhesion molecules that are important for synapse assembly and function. At excitatory synapses, NLGN1 mediates transsynaptic binding with neurexin, a presynaptic cell adhesion molecule, and also binds to PSD-95, although the relevance of the PSD-95 interaction is not clear. We now show that disruption of the NLGN1 and PSD-95 interaction decreases surface expression of NLGN1 in cultured neurons. Furthermore, PKA phosphorylates NLGN1 on S839, near the PDZ ligand, and dynamically regulates PSD-95 binding. A phosphomimetic mutation of NLGN1 S839 significantly reduced PSD-95 binding. Impaired NLGN1/PSD-95 binding diminished synaptic NLGN1 expression and NLGN1-mediated synaptic enhancement. Our results establish a phosphorylation-dependent molecular mechanism that regulates NLGN1 and PSD-95 binding and provides insights into excitatory synaptic development and function.PKA | NLGN1 | phosphorylation | PSD-95 P SD-95, a member of membrane-associated guanylate kinases (MAGUK) protein family, is a major constituent of glutamatergic excitatory synapses and is specifically enriched at the postsynaptic density (PSD) (1). A large number of channels, receptors, and adhesion molecules bind to the PSD-95/Discs large/ZO-1 (PDZ), Src-homology-3, and guanylate kinase (GK) domains of PSD-95 (1, 2). As a scaffolding protein at excitatory synapses, PSD-95 has been intensively studied vis a vis the organization of glutamatergic postsynaptic signaling. In fact, synaptic expression and transmission of N-methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) are regulated by PSD-95 via direct physical interaction or coordination with auxiliary proteins (3-6). Numerous studies have demonstrated critical roles of PSD-95 in the formation and maintenance of dendritic spines, and recent reports have focused on PSD-95 and the molecular mechanisms underlying synapse maturation and plasticity.Neuroligins (NLGNs) are type I membrane proteins and postsynaptic cell adhesion molecules. NLGNs were initially reported as endogenous neurexin (NRXN) ligands (7,8). NLGNs and NRXNs form a transsynaptic interaction, which is important for spinogenesis and functional synapse formation (9, 10). Five NLGN isoforms (NLGN1, NLGN2, NLGN3, NLGN4X, and NLGN4Y) are identified in humans (7,11). In fact, all identified NLGN isoforms show high similarity in amino acid sequence. In addition, the defined protein binding domains in the cytoplasmic region, including the PDZ ligand, are well conserved in all NLGN isoforms (11,12). However, isoform-specific mechanisms regulating synaptic localization are not fully understood.Because NLGN1 and PSD-95 are both localized to excitatory synapses, and their direct interaction via third PDZ domain of PSD-95 was identified in an early study (13), PSD-95 and NLGN1 have been investiga...

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Nuclear access of DNlg3 c-terminal fragment and its function in regulating innate immune response genes

Xie

Liu

et al. 2023

Biochemical and Biophysical Research Communications

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Posttranslational modifications of neuroligins regulate neuronal and glial signaling

Cited by 32 publications

References 53 publications

Optogenetic control of excitatory post-synaptic differentiation through neuroligin-1 tyrosine phosphorylation

Optogenetic control of excitatory post-synaptic differentiation through neuroligin-1 tyrosine phosphorylation

PSD-95 binding dynamically regulates NLGN1 trafficking and function

Nuclear access of DNlg3 c-terminal fragment and its function in regulating innate immune response genes

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