8.A.117.  The Neuroligin (Nlg) Family 

Activity-dependent proteolytic cleavage of neuroligins revealed a broader role for neuroligins than just synaptic 'glue'. The cleaved extracellular fragments of neuroligins may promote glioma formation. Cell signaling mediated by the cleavage products of neuroligins suggest novel and important roles for neuroligins in neuro-glial signaling. Neuroligin isoforms are dynamically regulated by posttranslational events including phosphorylation, glycosylation and activity-dependent cleavage (Jeong et al. 2017). It appears that neuroligins are homologous to many esterases, and therefore, they may have esterase activity.

Physical interactions in the synapse, mediated by synaptic adhesion molecules such as neiroligins, are essential for synaptogenesis. The regulation of adhesion molecules and their interactions with other synaptic proteins affect synapse formation and synaptic function. Bemben et al. 2015 reviewed the neuroligins, which bind to their presynaptic partner neurexin across the synaptic cleft. A structural overview of neuroligins, including their intermolecular interactions and molecular modifications that occur within a synapse as well as their physiological functions were presented by Bemben et al. 2015. neuroligins are constituents of GABAA receptor complexes (Tomita 2019).



Bemben, M.A., S.L. Shipman, R.A. Nicoll, and K.W. Roche. (2015). The cellular and molecular landscape of neuroligins. Trends Neurosci 38: 496-505.

Graf, E.R., X. Zhang, S.X. Jin, M.W. Linhoff, and A.M. Craig. (2004). Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins. Cell 119: 1013-1026.

Jedlicka, P., J. Muellerleile, and S.W. Schwarzacher. (2018). Synaptic Plasticity and Excitation-Inhibition Balance in the Dentate Gyrus: Insights from Recordings in Neuroligin-1, Neuroligin-2, and Collybistin Knockouts. Neural Plast 2018: 6015753.

Jeong, J., J.D. Paskus, and K.W. Roche. (2017). Posttranslational modifications of neuroligins regulate neuronal and glial signaling. Curr Opin Neurobiol 45: 130-138.

Katzman, A. and C.M. Alberini. (2018). NLGN1 and NLGN2 in the prefrontal cortex: their role in memory consolidation and strengthening. Curr Opin Neurobiol 48: 122-130.

Maro, G.S., S. Gao, A.M. Olechwier, W.L. Hung, M. Liu, E. Özkan, M. Zhen, and K. Shen. (2015). MADD-4/Punctin and Neurexin Organize C. elegans GABAergic Postsynapses through Neuroligin. Neuron. 86: 1420-1432.

Sun, M., G. Xing, L. Yuan, G. Gan, D. Knight, S.I. With, C. He, J. Han, X. Zeng, M. Fang, G.L. Boulianne, and W. Xie. (2011). Neuroligin 2 is required for synapse development and function at the Drosophila neuromuscular junction. J. Neurosci. 31: 687-699.

Tomita, S. (2019). Molecular constituents and localization of the ionotropic GABA receptor complex in vivo. Curr Opin Neurobiol 57: 81-86. [Epub: Ahead of Print]

Tu, H., B. Pinan-Lucarré, T. Ji, M. Jospin, and J.L. Bessereau. (2015). C. elegans Punctin Clusters GABA(A) Receptors via Neuroligin Binding and UNC-40/DCC Recruitment. Neuron. 86: 1407-1419.

Wang, Y., Y.C. Zhang, K.X. Zhang, Z.Q. Jia, T. Tang, L.L. Zheng, D. Liu, and C.Q. Zhao. (2021). Neuroligin 3 from common cutworm enhances the GABA-induced current of recombinant SlRDL1 channel. Pest Manag Sci. [Epub: Ahead of Print]

Xiong, L.L., L.L. Xue, Y.J. Chen, R.L. Du, Q. Wang, S. Wen, L. Zhou, T. Liu, T.H. Wang, and C.Y. Yu. (2021). Proteomics Study on the Cerebrospinal Fluid of Patients with Encephalitis. ACS Omega 6: 16288-16296.

Zhang, B., O. Gokce, W.D. Hale, N. Brose, and T.C. Südhof. (2018). Autism-associated neuroligin-4 mutation selectively impairs glycinergic synaptic transmission in mouse brainstem synapses. J Exp Med 215: 1543-1553.


TC#NameOrganismal TypeExample

Neuroligan-2 of 835 aas and 2 TMSs, one N-terminal and one near the C-terminus. Postsynaptic proteins localize to excitatory (neuroligin-1) and inhibitory synapses (neuroligin-2 and collybistin). The lack of neuroligin-1 leads to deficient synaptic plasticity and reduced excitation but normal granule cell output, but the lack of neuroligin-2 and/or collybistin reduces inhibition, resulting in a shift towards excitation of the dentate circuitry (Jedlicka et al. 2018). Neuroligan-2 is a constituent of the GABAA receptor (TC# 1.A.9.5.2) (Tomita 2019). It might be a biomarker for the diagnosis of encephalitis (Xiong et al. 2021).

Neuroligin 2 of Homo sapiens


Neuroligin-1, NGLN1, of 840 aas and 2 TMSs, N-terminal and near the C-terminus.  NGLN1 plays a role in memory by influencing synaptic transmission (Katzman and Alberini 2018).

NGLN1 of Homo sapiens



Neuroliligin-4, NLGN4, of 816 aas and 2 TMSs, N- and C-terminal.  Plays a role in autism by promoting glycinergic synaptic transmission in brainstem synapses (Zhang et al. 2018).

NLGN4 of Homo sapiens


Neuroligin-2, Nlg2, of 1248 aas and at least 2 TMSs, N-terminal and near the C-terminus, but as many as 4 more potential TMSs can be found near the N-terminus. Required for synapse formation and function (Sun et al. 2011).

NLGN2 of Drosophila melanogaster


Neuroligin-1 (NGLN1) of 798 aas and 2 TMSs. Iit is involved in cell-cell-interactions by forming intercellular junctions through binding to beta-neurexins, and it plays a role in the clustering of the GABA(A) receptor Unc-49 at postsynaptic sites in neuromuscular junctions via interactions with madd-4 and neurexin, nrx-1. It is is thereby required for normal GABAergic synaptic transmission (Maro et al. 2015, Tu et al. 2015).

NGLN1 of Caenorhabditis elegans


Neuroligin-3, NLGN-3, of 848 aas and up to 8 TMSs in a possible 2 + 2 + 2 + 2 TMS arrangement. It is a cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members. It plays a role in synapse function and synaptic signal transmission, and may mediate its effects by clustering other synaptic proteins. It may also promote the initial formation of synapses, but is not essential for this. It may also play a role in glia-glia or glia-neuron interactions in the developing peripheral nervous system. Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins (Graf et al. 2004). Neuroligin 3 from the common cutworm enhances the GABA-induced current of recombinant SlRDL1 channels (TC family 1.A.9) (Wang et al. 2021).


Neuroligin-3 of Homo sapiens