Soluble Ectodomain of Neuroligin 1 Decreases Synaptic Activity by Activating Metabotropic Glutamate Receptor 2

Gjørlund, Michelle D.; Carlsen, Eva Meier; Kønig, Andreas B.; Dmytrieva, Oksana; Petersen, Anders Victor; Jacobsen, Jacob P. R.; Berezin, Vladimir; Perrier, Jean‐François; Owczarek, Sylwia

doi:10.3389/fnmol.2017.00116

Cited by 7 publications

(5 citation statements)

References 36 publications

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“…Neurexins and neuroligins are important transmembrane adhesion proteins in the regulation of synapse function. 11 , 43 – 46 The expressions of neuroligin1 and neuroligin2 in the central nervous system are restricted to excitatory and inhibitory synapses, respectively. 18 , 47 – 49 Neuroligin1 is enriched at the postsynaptic densities of excitatory synapses containing the scaffolding protein PSD-95.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of neuroligin1 ameliorates postoperative pain through inhibiting neuroligin1/postsynaptic density 95-mediated synaptic targeting of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor GluA1 subunits in rat dorsal horns

Guo

et al. 2018

Mol Pain

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Neuroligin1 is an important synaptic cell adhesion molecule that modulates the function of synapses through protein–protein interactions. Yet, it remains unclear whether the regulation of synaptic transmission in the spinal cord by neruoligin1 contributes to the development of postoperative pain. In a rat model of postoperative pain induced by plantar incision, we conducted Western blot study to examine changes in the expression of postsynaptic membrane of neuroligin1, postsynaptic density 95 (PSD-95), and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor GluA1 and GluA2 subunits in the spinal cord dorsal horn after injury. The interaction between neuroligin1 and PSD-95 was further determined by using coimmunoprecipitation. Protein levels of neuroligin1 and GluA1, but not GluA2 and PSD-95, were significantly increased in the postsynaptic membrane of the ipsilateral dorsal horn at 3 h and 1 day after incision, as compared to that in control group (naïve). A greater amount of PSD-95 was coimmunoprecipitated with neuroligin1 at 3 h after incision than that in the control group. Intrathecal administration of small interfering RNAs (siRNAs) targeting neuroligin1 suppressed the expression of neuroligin1 in the spinal cord. Importantly, pretreatment with intrathecal neuroligin1 siRNA2497, but not scrambled siRNA or vehicle, prevented the upregulation of GluA1 expression at 3 h after incision, inhibited the enhanced neuroligin1/PSD-95 interaction, and attenuated postoperative pain. Together, current findings suggest that downregulation of spinal neuroligin1 expression may ameliorate postoperative pain through inhibiting neuroligin1/PSD-95 interaction and synaptic targeting of GluA1 subunit. Accordingly, spinal neuroligin1 may be a potential new target for postoperative pain treatment.

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Section: Discussionmentioning

confidence: 99%

Downregulation of neuroligin1 ameliorates postoperative pain through inhibiting neuroligin1/postsynaptic density 95-mediated synaptic targeting of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor GluA1 subunits in rat dorsal horns

Guo

et al. 2018

Mol Pain

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“…For example, proteolytic cleavage of Nlg-1 prevents its surface expression, leading to the destabilization of trans-synaptic Nrx–Nlg complexes [ 55 , 56 ]. Furthermore, the extracellular fragments of Nlg-1 generated through its proteolytic cleavage can bind to presynaptic metabotropic glutamate receptors, ultimately leading to their activation and the suppression of glutamate release, thereby reducing synaptic strength [ 57 ]. Likewise, the induction of Nlg-3 proteolytic cleavage by protein kinase C results in reduced synaptic strength that can be counteracted by the prevention of cleavage.…”

Section: The Neurexin–neuroligin Mediated Trans-synaptic Modulationmentioning

confidence: 99%

Modulation of Trans-Synaptic Neurexin–Neuroligin Interaction in Pathological Pain

Guo

Guan

et al. 2022

Cells

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Synapses serve as the interface for the transmission of information between neurons in the central nervous system. The structural and functional characteristics of synapses are highly dynamic, exhibiting extensive plasticity that is shaped by neural activity and regulated primarily by trans-synaptic cell-adhesion molecules (CAMs). Prototypical trans-synaptic CAMs, such as neurexins (Nrxs) and neuroligins (Nlgs), directly regulate the assembly of presynaptic and postsynaptic molecules, including synaptic vesicles, active zone proteins, and receptors. Therefore, the trans-synaptic adhesion mechanisms mediated by Nrx–Nlg interaction can contribute to a range of synaptopathies in the context of pathological pain and other neurological disorders. The present review provides an overview of the current understanding of the roles of Nrx–Nlg interaction in the regulation of trans-synaptic connections, with a specific focus on Nrx and Nlg structures, the dynamic shaping of synaptic function, and the dysregulation of Nrx–Nlg in pathological pain. Additionally, we discuss a range of proteins capable of modulating Nrx–Nlg interactions at the synaptic cleft, with the objective of providing a foundation to guide the future development of novel therapeutic agents for managing pathological pain.

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“…Notably, the authors showed that MMP-9-dependent shedding of NLGN1 leads to the destabilization of presynaptic NRX1β and downregulation of synaptic transmission. Recent data suggest that the soluble extracellular domain of NLGN1 binds to metabotropic glutamate receptor 2 (mGluR2), and thereby decreases synaptic strength [ 89 ].…”

Section: Regulation Of Mmp-9 Substrates By Small Rho Gtpasesmentioning

confidence: 99%

MMP-9 Signaling Pathways That Engage Rho GTPases in Brain Plasticity

Figiel

Kruk

Zaręba-Kozioł

et al. 2021

Cells

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The extracellular matrix (ECM) has been identified as a critical factor affecting synaptic function. It forms a functional scaffold that provides both the structural support and the reservoir of signaling molecules necessary for communication between cellular constituents of the central nervous system (CNS). Among numerous ECM components and modifiers that play a role in the physiological and pathological synaptic plasticity, matrix metalloproteinase 9 (MMP-9) has recently emerged as a key molecule. MMP-9 may contribute to the dynamic remodeling of structural and functional plasticity by cleaving ECM components and cell adhesion molecules. Notably, MMP-9 signaling was shown to be indispensable for long-term memory formation that requires synaptic remodeling. The core regulators of the dynamic reorganization of the actin cytoskeleton and cell adhesion are the Rho family of GTPases. These proteins have been implicated in the control of a wide range of cellular processes occurring in brain physiology and pathology. Here, we discuss the contribution of Rho GTPases to MMP-9-dependent signaling pathways in the brain. We also describe how the regulation of Rho GTPases by post-translational modifications (PTMs) can influence these processes.

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Soluble Ectodomain of Neuroligin 1 Decreases Synaptic Activity by Activating Metabotropic Glutamate Receptor 2

Cited by 7 publications

References 36 publications

Downregulation of neuroligin1 ameliorates postoperative pain through inhibiting neuroligin1/postsynaptic density 95-mediated synaptic targeting of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor GluA1 subunits in rat dorsal horns

Downregulation of neuroligin1 ameliorates postoperative pain through inhibiting neuroligin1/postsynaptic density 95-mediated synaptic targeting of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor GluA1 subunits in rat dorsal horns

Modulation of Trans-Synaptic Neurexin–Neuroligin Interaction in Pathological Pain

MMP-9 Signaling Pathways That Engage Rho GTPases in Brain Plasticity

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