Neurexins (NRXNs) and neuroligins (NLGNs) are best characterized synaptic cell-adhesion molecules. They are part of excitatory glutamatergic and inhibitory GABAergic synapses in mammalian brain, mediate trans-synaptic signaling, and shape neural network properties by specifying synaptic functions. As cell-adhesion molecules, NRXNs and NLGNs probably function by binding to each other and by interacting with intracellular PDZ-domain proteins, but the precise mechanisms involved and their relation to synaptic transmission remain unclear. The binding of NRXNs and NLGNs to their partners, helps to align the pre-synaptic release machinery and post-synaptic receptors. The importance of neurexins and neuroligins for synaptic function is evident from the dramatic deficits in synaptic transmission in mice lacking Nrxns or Nlgns. In humans, alterations in NRXNs or NLGNs genes are implicated in autism and other cognitive diseases, connecting synaptic cell adhesion to cognition and its disorders (Sudhof 2008, Craig et al. 2006, Craig & Kang 2007).
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NMDAR complex consists of two NR1 subunits and two NR2 subunits. Each subunit has extensive C terminal tail that is modified by series of protein kinases and protein phosphatases. The NR1 subunits binds co-agonist glycine while the NR2 subunit binds glutamate. Hence the activation of NR1/NR2 containing NMDA receptor complexes are activated upon depolarization of the membrane and binding of both glycine and glutamate. The dual requirement of membrane depolarization and agonist binding facilitate coincidence detection by NMDA receptors that ensures activation of both pre-synaptic and post-synaptic cell. NR1/NR2 containing NMDA receptors are highly Ca2+ permeable and subjected to a voltage dependent Mg2+ block.
NMDA receptors are multimeric glutamate-gated cation channels, which are major constituents of the postsynaptic density (PSD). PSD-95/SAP90 protein is a member of the membrane-associated guanylate kinase (MAGUK) family and a prominant component of the PSD and associates with NMDA receptors. The interaction is mediated by binding of the C-terminus of the NMDA receptor subunits to the first two PDZ (also known as GLGF or DHR) domains of PSD-95 (Kornau et al. 1995, Niethammer et al. 1996). PSD-95 acts as a scaffolding protein in NMDA receptor signalling by bringing together NMDA receptor and various proteins like enzyme neuronal nitric oxide synthase (nNOS) (Brenman et al. 1996), SynGAP (Kim et al. 1998), GKAP (Kim et al. 1997), SHANK (Naisbitt et al. 1999) and multiple non-receptor tyrosine kinases (Sala & Sheng 1999). In this way, the multidomain PSD-95 molecule connects NMDA receptors to a variety of intracellular signaling proteins and anchors the whole complex to the postsynaptic density. PSD-95 subfamily includes other three more members: PSD-93/chapsyn-110, SAP97/hDlg, and SAP102. All except SAP97 appear to be components of the PSD and associated with NMDA receptors.
Guanylate kinase-associated protein (GKAP; also known as synapse-associated 42 protein 90-postsynaptic density-95-associated protein (SAPAP) and Discs-large-associated 43 protein (DAP) family proteins) a synaptic protein is one of the major constituent of the postsynaptic density (PSD). GKAP binds directly to the GK (guanylate kinase-like) domain of the four known members of the PSD-95 (postsynaptic density protein 95) family (Kim et al. 1997, Naisbitt et al. 1997, Takeuchi et al. 1997). GKAP is therefore one of the major scaffold proteins organizing glutamate receptors in the PSD.
Homer with its EVH1 domain binds to proline-rich motif of Shank family members. Shank and Homer coimmunoprecipitate from brain and colocalize at postsynaptic densities. Shank uses distinct domains to bind to GKAP and Homer, thus it can bridge between these two proteins. Thus, Shank may cross-link Homer and PSD-95 complexes in the PSD and play a role in the signaling mechanisms of both mGluRs and NMDA receptors (Tu et al. 1999).
Neuroligins (NLGNs) bind to the third PDZ domain of postsynaptic density (PSD)-95 whereas NMDA receptor and K+ channels interact with the first and the second PDZ domains. The cytoplasmic domains of all three neuroligins interacts with the NH2-terminus of PSD-95 and its homologs PSD-93 and SAP102, which contains the three PDZ domains (Irie et al. 1997).
The mammalian genome contains three NRXN genes (NRXN1, NRXN2 and NRXN3), each of which produce from independent promoters a longer alpha- and a shorter beta neurexin isoform. Furthermore, extensive alternative splicing at five canonical positions generates thousands of NRXN isoforms. In situ hybridizations showed that different alpha and beta-NRXNs are co-expressed in the same class of neurons, but that each type of NRXN is differentially distributed among different classes of neurons (Ullirich et al. 1995, Sudhof 2009, Missler et al. 2012). Neuroligins (NLGNs) are endogenous NRXN ligands. NLGNs are expressed from four genes in vertebrates (NLGN-1 to -4). All NLGNs are alternatively spliced at a single canonical position (referred to as SS A) (Boucard et al. 2005, Ichtchenko et al. 1996). In contrast to neurexins, neuroligins are specifically localized to particular synapses. NLGN1 is only present at excitatory synapses (Song et al. 1999), NLGN2 and NLGN4 at inhibitory synapses (Varoqueaux et al. 2004, Hoon et al. 2011), whereas NLGN3 is present at both excitatory and inhibitory synapses (Budreck and Scheiffele 2007). alpha- and beta-neurexins both bind to all neuroligins to form cell adhesion complexes (Boucard et al. 2005). alpha-NRXNs with thier sixth LNS (laminin, neurexin and sex hormone-binding globulin-like) domain and beta-NRXNs with their single LNS domain bind to the lateral sides of the NLGNs esterase-homology domain (Fabrichny et al. 2007, Arac et al. 2007, Chen et al. 2008, Boucard et al. 2005, Reissner et al. 2008).
Homer dimerizes via the coiled-coil domains to form a rod with EVH1 domains on either end. It could interact with mGluRs on one end and with the other EVH1 domain can bind to Shank proteins linking the two receptors together (Hayashi et al. 2009).
Synaptotagmins (SYTs) are transmembrane proteins involved in membrane trafficking and calcium-dependent exocytosis of synaptic vesicles at the synapse. SYTs may mediate this by binding to presynaptic proteins, the neurexins (NRXNs) (Perin 1994, Hata et al. 1993, Petrenko et al. 1991). The interaction between these two proteins may mediate part of the recognition of presynaptic active sites by synaptic vesicles or may regulate neurotransmitter release (Perin 1996).
Spine-Associated RapGAP (SPAR) is a postsynaptic Rap-specific GTPase-activating protein (RapGAP) that reorganizes actin cytoskeleton and drives dentritic spine head growth. SPAR interacts with the guanylate kinase-like (GK) domain of Disks large homolog proteins (DSGs) forming a complex with NMDA receptors in brain (Pak et al. 2001).
SHANK with its ankyrin repeats has been found to bind SHARPIN a molecule that can form homomers. SHARPIN is another PSD protein enriched at synaptic sites in mature neurons and may be involved in the formation and maintenance of excitatory synaptic structures (Lim et al. 2001).
CASK (Calcium/calmodulin-dependent serine protein kinase) a multidomain synaptic scafolding protein binds to the extreme C terminus of neurexins (Hata et al. 1996). In brain, CASK binds to MINT1 with its CaM kinase domain, and all three Velis with the region between the CaM kinase and PDZ domains to form a tight tripartite complex (Butz et al. 1998). This tripartite complex may serve as nucleation site for the assembly of synaptic plasma membrane proteins. Recruitment of this tripartite complex to the plasma membrane by binding to neurexins may be involved in synaptic vesicle traffic.
The cytoplasmic PDZ (PSD-95, Dlg, and ZO-1/2 domain) domain of Neurexin interacts with the intracellular vesicle trafficking protein MUNC18/STXB1 (syntaxin binding peotein) via a multiprotein complex that involves MINT1 and MINT2. MUNC18, a sec1-like protein that is essential for neurotransmitter release exists in complex with Syntaxin (STX1A) and MINT1 and MINT2 in the nervous system (Okamoto & Sudhof 1997, Biederer & Sudhof 2000).
Spine-Associated RapGAP (SPAR) interacts with a PDZ-LIM domain family protein called PDZ and LIM domain 5 (PDLIM5), formerly known as Enigma Homolog (ENH). PDLIM5 is expressed postsynaptically in excitatory pyramidal neurons of the hippocampus and associates with SPAR protein in the brain. In hippocampal neurons, PDLIM5 promotes decreased dendritic spine size, opposite to the effect of SPAR overexpression that causes spine head enlargement.
Single nucleotide polymorphisms in PDLIM5 have been associated with schizophrenia, depression, and bipolar disorder (Kato et al. 2005, Li et al. 2008, Liu et al. 2008), although the physiological functions of PDLIM5 are not well understood.
Homer proteins are closely related neuronal scaffolding molecules that selectively binds the C-terminus of group 1 metabotropic or heterotrimeric GTP-binding protein-linked glutamate receptors (mGluR1a and mGluR5) and are enriched at excitatory synapses (Brakeman et al. 1997, Xiao et al. 1998). Homer proteins contain an amino-terminal EVH1 domain followed by a rod-shaped coiled-coil domain. The EVH1 domain of Homer can bind the proline rich motifs in mGluRs and the inositol 1,4,5-trisphosphate (IP3) receptors, thereby linking these receptors in a signalling complex (Tu et al. 1998, 1999).
Disks large homolog proteins (DLGs, Post synaptic density proteins) 2, 3 and 4 interact with BEGAIN (Brain-enriched Guanylate Kinase-associated Protein) via their guanylate kinase-like (GK) domain. BEGAIN is specifically expressed in brain and enriched in the PSD fraction and may be involved in the organization of the components of synaptic junctions (Deguchi et al. 2001).
PSD-95 interacts with GKAP through its GK domain (Kim et al. 1997). In turn, the C-terminus of GKAP binds to the Shank family of PDZ-containing scaffold proteins. The Shank family of proteins is highly enriched in the postsynaptic density (PSD) of excitatory synapses in brain. There are three known SHANK proteins: SHANK1, SHANK2, and SHANK3. SHANK contains multiple domains for protein-protein interactions, including ankyrin repeats, SH3 domain, PDZ domain, SAM domain, and an extensive proline-rich region (Sheng & Kim 2000). Shank may function as a scaffold protein in the PSD, potentially cross-linking NMDA receptor or Neuroligin:PSD-95 complexes and coupling them to regulators of the actin cytoskeleton (Naisbitt et al.1999).
The protein 4.1 family includes four well-defined members: erythroid protein 4.1 (4.1R), the bestknown and characterized member, 4.1G (general), 4.1N (neuronal), and 4.1 B (brain). Protein 4.1N is a neuronal homologue of erythrocyte membrane cytoskeletal protein 4.1 (4.1R). Protein 4.1N can stabilize the plasticity of the neuronal membrane via interactions with the spectrin-actin-based skeleton, integral membrane channels and receptors, and membrane-associated guanylate kinases (Diakowski et al. 2006). This brain-specific protein 4.1N isoform intercts with CASK and recruits actin and spectrin (Biederer & Sudhof 2001).
At the PSD (postsynaptic density), activity-dependent reorganizations of the cortical actin cytoskeleton are hypothesized to play a role in synaptic plasticity. Drebrin-like protein (DBNL) (also referred as Filamentous actin (F-actin)-binding protein 1 (ABP1)), which controls Arp2/3 complex-mediated actin nucleation binds to postsynaptic scaffold proteins of the ProSAP (proline-rich synapse-associated protein 1)/Shank family. This DBNL–ProSAP/Shank complexes serve to connect synaptic signal reception to postsynaptic structural plasticity via rearrangements of the actin cytoskeleton in spines (Haeckel et al. 2008).
In neurons, CASK forms a stable tripartite complex with brain-enriched Veli proteins and brain-specific Mint1 and anchors this complex to neurexins (Butz et al. 1998). CASK also binds to a brain-enriched isoform of protein 4.1, and nucleates local assembly of actin/spectrin filaments. Neurexins are recruited together with CASK and protein 4.1 into these actin filaments and thus intercellular junctions initiated by neurexins with neuroligins are at least partially coupled to the actin cytoskeleton (Biederer & Sudhof 2001).
The LRRTM (leucine-rich repeat (LRR) transmembrane neuronal) are a small family of paralogous LRR containing cell surface receptors. This family has four members (LRRTM 1-4) that share similar domain structure with an extracellular domain containing ten extracellular leucine-rich repeats that mediate protein-protein interactions, followed by a single transmembrane domain and a short c-terminal sequence containing a class I PDZ-domain-binding motif. LRRTMs are predominantely expressed in the nervous system. All four LRRTMs family members are post-synaptic localized and bind specifically to presynaptic alpha and beta-Neurexins (NRXNs) lacking an insert at splice site S4 (Siddiqui et al. 2010). Neuroligins bind NRXN containing or lacking an insert in S4, LRRTMs bind only NRXNs lacking an insert in this splicing site (de Wit et al. 2009, Ko et al. 2009).
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DataNodes
receptor
complex:DLG2,DLG3,DLG4:SPAR:PDLIM5receptor
complex:DLG2,DLG3,DLG4:SPARreceptor
complex:DLG2,DLG3,DLG4receptor
complex:PSD-95:BEGAINdimers:CASK:Protein
4.1dimers:PSD-95
membersAnnotated Interactions
receptor
complex:DLG2,DLG3,DLG4:SPAR:PDLIM5receptor
complex:DLG2,DLG3,DLG4:SPARreceptor
complex:DLG2,DLG3,DLG4:SPARreceptor
complex:DLG2,DLG3,DLG4receptor
complex:DLG2,DLG3,DLG4receptor
complex:DLG2,DLG3,DLG4receptor
complex:PSD-95:BEGAINdimers:CASK:Protein
4.1dimers:PSD-95
membersdimers:PSD-95
membersNeuroligins (NLGNs) are endogenous NRXN ligands. NLGNs are expressed from four genes in vertebrates (NLGN-1 to -4). All NLGNs are alternatively spliced at a single canonical position (referred to as SS A) (Boucard et al. 2005, Ichtchenko et al. 1996). In contrast to neurexins, neuroligins are specifically localized to particular synapses. NLGN1 is only present at excitatory synapses (Song et al. 1999), NLGN2 and NLGN4 at inhibitory synapses (Varoqueaux et al. 2004, Hoon et al. 2011), whereas NLGN3 is present at both excitatory and inhibitory synapses (Budreck and Scheiffele 2007). alpha- and beta-neurexins both bind to all neuroligins to form cell adhesion complexes (Boucard et al. 2005). alpha-NRXNs with thier sixth LNS (laminin, neurexin and sex hormone-binding globulin-like) domain and beta-NRXNs with their single LNS domain bind to the lateral sides of the NLGNs esterase-homology domain (Fabrichny et al. 2007, Arac et al. 2007, Chen et al. 2008, Boucard et al. 2005, Reissner et al. 2008).