Neurexin-1 (NRXN1) is a neuron-specific, presynaptic single-pass type I membrane protein and a central organizer of synapses. The gene uses two promoters: the upstream promoter produces the long neurexin-1-alpha isoforms described by this entry, whose extracellular region has six laminin/neurexin/sex-hormone-binding globulin (LNS) domains interspersed with three EGF-like repeats, and an internal promoter produces the short neurexin-1-beta isoforms (separate UniProt entry P58400) that carry only the sixth LNS domain; both share a heparan-sulfate-modified stalk, a transmembrane helix and a short cytoplasmic tail ending in a PDZ-binding motif. Extensive alternative splicing, most importantly at splice site 4 (SS4) in LNS6, controls which partners are bound. Through Ca2+-dependent binding of its LNS domains, NRXN1 forms cleft-spanning adhesion complexes with postsynaptic neuroligins (NLGN1-4), LRRTMs (SS4-lacking forms), latrophilins/CIRLs, dystroglycan and, via secreted cerebellins (SS4-containing forms), with delta-type glutamate receptors; alpha isoforms additionally bind neurexophilins. These complexes hold pre- and postsynaptic membranes together and signal in both directions: neurexin presented to dendrites induces clustering of glutamatergic and GABAergic postsynaptic components, and postsynaptic ligands induce presynaptic differentiation through neurexin. Intracellularly the tail binds PDZ scaffolds such as CASK and Mints. Alpha-neurexins are essential for Ca2+-triggered neurotransmitter release, organizing presynaptic terminals by functionally coupling Ca2+ channels to the release machinery, yet they are largely dispensable for synapse formation per se, so neurexins act mainly as context-dependent specifiers of synaptic properties. Neurexin-1 was first identified as the receptor for the spider venom neurotoxin alpha-latrotoxin. Heterozygous NRXN1 deletions confer risk for autism, schizophrenia and intellectual disability, and biallelic loss causes Pitt-Hopkins-like syndrome 2.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004888 transmembrane signaling receptor activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA from the neurexin clade node PTN002227321. Neurexins act as the presynaptic receptor for postsynaptic organizers such as LRRTM2 and neuroligins, whose presynaptic-differentiation activity requires neurexin. Reason: The node placement is sound: neurexins in vertebrates and invertebrates bind postsynaptic ligands and neurexin knockdown abolishes LRRTM2-induced presynaptic differentiation, i.e. neurexin behaves as a receptor. However, how ligand binding is transduced across the presynaptic membrane is not established, and most of what neurexin does is as a bidirectional adhesion/organizer molecule (it equally acts as the ligand that induces postsynaptic differentiation). The adhesion-mediator and trans-synaptic signaling terms capture the core activity better, so this is retained as non-core. Supporting Evidence: PMID:20064388 LRRTM2 binds to both Neurexin 1alpha and Neurexin 1beta, and shRNA-mediated knockdown of Neurexin1 abrogates LRRTM2-induced presynaptic differentiation. PMID:20064387 two unrelated postsynaptic cell-adhesion molecules, LRRTMs and neuroligins, unexpectedly bind to neurexins as the same presynaptic receptor PMID:15620359 We show here that neurexin alone is sufficient to induce glutamate postsynaptic differentiation in contacting dendrites. |
| GO:0005246 calcium channel regulator activity | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS from mouse Nrxn1, whose source annotation is an IGI from alpha-neurexin double/triple knockouts showing reduced synaptic Ca2+ channel function. Reason: Alpha-neurexin deletion reduces synaptic Ca2+ current and Ca2+-triggered release, but the effect is indirect: cell-surface Ca2+ channel number is normal, and recordings from melanotrophs, transfected HEK cells and brainstem neurons showed that alpha-neurexins do not affect Ca2+ channel activation or inactivation directly; they appear to couple channels to release-ready vesicles. A molecular-function claim that NRXN1 itself modulates channel activity goes beyond this evidence. The biology is better represented at the process level (Ca2+-triggered neurotransmitter secretion). Supporting Evidence: PMID:12827191 Neurotransmitter release is impaired because synaptic Ca2+ channel function is markedly reduced, although the number of cell-surface Ca2+ channels appears normal. PMID:17035546 alpha-neurexins do not affect the activation or inactivation properties of Ca2+ channels directly but may be responsible for coupling them to release-ready vesicles and metabotropic receptors |
| GO:0005509 calcium ion binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from rat neurexin-1. LNS domains of neurexins carry Ca2+-binding sites (UniProt annotates Ca2+-binding residues in LNS2, LNS4 and LNS6) and ligand binding is Ca2+-dependent. Reason: Correct: mutating the LNS Ca2+-binding site abolishes dystroglycan binding, and neuroligin binding is Ca2+-dependent. Ca2+ acts as a structural cofactor at the ligand-binding edge of LNS domains rather than being the function in itself, so this is kept as a supporting, non-core activity. Supporting Evidence: PMID:11470830 As with the Ig fusion proteins, the GST fusion protein bound dystroglycan in a Ca2+-dependent manner; binding was completely abolished by the Ca2+-binding site mutant. file:human/NRXN1/NRXN1-uniprot.txt interactions with NLGN1, NLGN2, NLGN3 and NLGN4L are calcium-dependent |
| GO:0005515 protein binding | IPI PMID:11152476 The neural cell recognition molecule neurofascin interacts w... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (SDCBP2/syntenin-2). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:11152476 syntenin-2alpha, which interacts with neurexin I PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005515 protein binding | IPI PMID:12421765 Protein-protein interactions between large proteins: two-hyb... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (PDZD2). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:12421765 Cytoplasmic domains of KIAA transmembrane proteins (>1000 amino acids) were used as bait for yeast two-hybrid screening. PMID:12421765 bearing a transmembrane region have the capability of binding to other KIAA proteins containing domains (e.g., PDZ, SH3, rhoGEF, and spectrin) PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (GRID2IP/delphilin). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (PDZD2). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (MPDZ). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (DLG4/PSD-95). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (TJP1/ZO-1). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (DLG1/SAP97). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (IL16 (pro-IL-16 PDZ domains)). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (SCRIB). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (DLG2/PSD-93). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (PDZK1). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (FRMPD2). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (MAGI2). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (NHERF4/PDZD3). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (LNX2). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (PATJ). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (LNX1). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (DLG3/SAP102). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (MAGI1). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (APBA2/Mint2). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (GRIP2). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (WHRN/whirlin). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: IPI for an interaction between the NRXN1 cytoplasmic tail and a PDZ-domain protein (GRIP1). The NRXN1 C-terminus ends in the class II PDZ-binding motif ...EYYV, which is how neurexins recruit CASK, Mints and other presynaptic PDZ scaffolds. Reason: Bare protein binding is uninformative. The partner is a PDZ-domain protein and the assay probes the neurexin cytoplasmic tail/C-terminal PDZ-binding motif, so the evidence supports the more informative GO:0030165 PDZ domain binding. This is consistent with the classic finding that neurexin I binding to the PDZ-containing MAGUK CASK depends on the three C-terminal residues. Rewriting the term does not imply that every screen-detected PDZ partner is physiologically relevant at the synapse. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:36115835 we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer PMID:8786425 In neurexin I, this interaction is dependent on the C-terminal three residues. PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0005783 endoplasmic reticulum | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS (endoplasmic reticulum) from mouse Nrxn1; reflects biosynthetic/transit pools of a neuronal type I membrane protein rather than a site of action. Reason: The ISS source is mouse Nrxn1 (UniProtKB:Q9CS84). ORGANELLES ER check (2026-11-05), examined as a synthesis row: an earlier version of this reason said mouse GOA has no experimental annotation to this term, which is wrong for the ER. QuickGO (2026-11-05) shows mouse Nrxn1 carries an IDA to GO:0005783 from BHF-UCL (PMID:19036990, same curation date as this ISS), and rat Nrxn1 has the same ISS/ISO chain. The donor paper (abstract only in cache) studies epitope-tagged neurexins in cultured mouse hippocampal neurons and shows biosynthetic transit: exit from the ER/Golgi needs the C-terminal PDZ-binding motif, and the two presumptive ER retention signals are inactive, so ER accumulation is expected only for constructs that cannot leave. That is transit plus retention of engineered mutants, which under the batch 1 transit rule (ATP1A1, ATP1A2, ATP2B2) is MARK_AS_OVER_ANNOTATED rather than KEEP_AS_NON_CORE; KEEP_AS_NON_CORE would apply if wild-type endogenous neurexin were shown in an ER pool, which the abstract does not report (the full text may show tagged wild-type neurexin in the ER in transit). NRXN1 is a single-pass type I protein with no ER-resident function; it acts at the presynaptic plasma membrane and active zone, so no ER membrane row is added (topology does not force a sub-compartment on a transit pool). Supporting Evidence: PMID:19036990 We also observed that exit of neurexins from the ER/Golgi and correct targeting require their PDZ-binding motif at the C terminus, whereas two presumptive ER retention signals are inactive. file:human/NRXN1/NRXN1-uniprot.txt SUBCELLULAR LOCATION: Presynaptic cell membrane PMID:1621094 An antibody to neurexin I showed highly concentrated immunoreactivity at the synapse. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: NRXN1 is a single-pass type I plasma membrane protein; IBA from the broad neurexin-family node. Reason: Uncontroversial. Wild-type human neurexin-1-alpha traffics efficiently to the cell surface; the functionally informative subcompartment is the presynaptic membrane/active zone membrane, also annotated. Supporting Evidence: PMID:21424692 Whereas wild-type Flag-neurexin-1Ξ± targeted efficiently to the cell surface, as detected by bright staining of unpermeabilized cells with Flag antibody, little or no insACGG mutant was detected on the cell surface file:human/NRXN1/NRXN1-uniprot.txt SUBCELLULAR LOCATION: Presynaptic cell membrane |
| GO:0005886 plasma membrane | IC PMID:21424692 Truncating mutations in NRXN2 and NRXN1 in autism spectrum d... | ACCEPT | Summary: Inferred by curator from the cell-surface IDA in the same paper. Reason: Surface staining of unpermeabilised cells expressing wild-type human neurexin-1-alpha establishes plasma membrane insertion. Supporting Evidence: PMID:21424692 Whereas wild-type Flag-neurexin-1Ξ± targeted efficiently to the cell surface, as detected by bright staining of unpermeabilized cells with Flag antibody, little or no insACGG mutant was detected on the cell surface |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from rat neurexin-1; plasma membrane localization. Reason: Consistent with the type I transmembrane topology and with direct surface-staining evidence for the human protein. Supporting Evidence: PMID:21424692 Whereas wild-type Flag-neurexin-1Ξ± targeted efficiently to the cell surface, as detected by bright staining of unpermeabilized cells with Flag antibody, little or no insACGG mutant was detected on the cell surface file:human/NRXN1/NRXN1-uniprot.txt SUBCELLULAR LOCATION: Presynaptic cell membrane |
| GO:0005886 plasma membrane | TAS PMID:1621094 Neurexins: synaptic cell surface proteins related to the alp... | ACCEPT | Summary: TAS from the neurexin discovery paper describing neurexins as neuronal cell-surface proteins with a single transmembrane region. Reason: Correct and uncontroversial. Supporting Evidence: PMID:1621094 Neurexins contain single transmembrane regions and extracellular domains with repeated sequences similar to sequences in laminin A, slit, and agrin, proteins that have been implicated in axon guidance and synaptogenesis. PMID:1621094 An antibody to neurexin I showed highly concentrated immunoreactivity at the synapse. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6794346 | ACCEPT | Summary: Reactome TAS placing NRXN1 at the plasma membrane in a neurexin partner-binding reaction. Reason: Correct; NRXN1 is a presynaptic plasma-membrane protein that binds neuroligins and LRRTMs extracellularly and CASK intracellularly. Supporting Evidence: Reactome:R-HSA-6794346 alpha- and beta-neurexins both bind to all neuroligins to form cell adhesion complexes PMID:21424692 Whereas wild-type Flag-neurexin-1Ξ± targeted efficiently to the cell surface, as detected by bright staining of unpermeabilized cells with Flag antibody, little or no insACGG mutant was detected on the cell surface |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6797554 | ACCEPT | Summary: Reactome TAS for plasma membrane arising from the neurexin/neuroligin/SHANK reaction set (this reaction concerns DBNL binding SHANK, with NRXN1 as a participant of the larger complex). Reason: The reaction itself is postsynaptic and says nothing specific about NRXN1, but the location it implies for NRXN1 (plasma membrane) is correct and independently established. Supporting Evidence: PMID:21424692 Whereas wild-type Flag-neurexin-1Ξ± targeted efficiently to the cell surface, as detected by bright staining of unpermeabilized cells with Flag antibody, little or no insACGG mutant was detected on the cell surface file:human/NRXN1/NRXN1-uniprot.txt SUBCELLULAR LOCATION: Presynaptic cell membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6797568 | ACCEPT | Summary: Reactome TAS placing NRXN1 at the plasma membrane in a neurexin partner-binding reaction. Reason: Correct; NRXN1 is a presynaptic plasma-membrane protein that binds neuroligins and LRRTMs extracellularly and CASK intracellularly. Supporting Evidence: Reactome:R-HSA-6797568 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 PMID:21424692 Whereas wild-type Flag-neurexin-1Ξ± targeted efficiently to the cell surface, as detected by bright staining of unpermeabilized cells with Flag antibody, little or no insACGG mutant was detected on the cell surface |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6797974 | ACCEPT | Summary: Reactome TAS placing NRXN1 at the plasma membrane in a neurexin partner-binding reaction. Reason: Correct; NRXN1 is a presynaptic plasma-membrane protein that binds neuroligins and LRRTMs extracellularly and CASK intracellularly. Supporting Evidence: Reactome:R-HSA-6797974 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 PMID:21424692 Whereas wild-type Flag-neurexin-1Ξ± targeted efficiently to the cell surface, as detected by bright staining of unpermeabilized cells with Flag antibody, little or no insACGG mutant was detected on the cell surface |
| GO:0007158 neuron cell-cell adhesion | IEA GO_REF:0000117 | MODIFY | Summary: ARBA machine-learning IEA for neuron cell-cell adhesion. Reason: Correct in essence: neurexins mediate adhesion between neurons by binding postsynaptic partners across the synaptic cleft. The adhesion is specifically between pre- and postsynaptic membranes, so the precise process is GO:0099560 synaptic membrane adhesion, as for the TAS row. Proposed replacements: synaptic membrane adhesion Supporting Evidence: PMID:16242404 neuroligin binding to alpha- and beta-neurexins mediates trans-synaptic cell adhesion but has distinct effects on synapse formation PMID:18923512 Neurexins and neuroligins are synaptic cell-adhesion molecules that connect presynaptic and postsynaptic neurons at synapses, mediate signalling across the synapse, and shape the properties of neural networks by specifying synaptic functions |
| GO:0007158 neuron cell-cell adhesion | TAS PMID:18923512 Neuroligins and neurexins link synaptic function to cognitiv... | MODIFY | Summary: TAS from a major review describing neurexins and neuroligins as synaptic cell-adhesion molecules that connect pre- and postsynaptic neurons. Reason: The adhesion NRXN1 mediates is specifically between the presynaptic and postsynaptic membranes, via trans-synaptic complexes with neuroligins, LRRTMs, cerebellin-GluD, latrophilins and dystroglycan. GO:0099560 synaptic membrane adhesion is the precise term (it is_a cell-cell adhesion, not a child of neuron cell-cell adhesion), is used for comparable synaptic adhesion molecules (NLGN1, PTPRD/Ptprd, Lrfn5, Slitrk family, teneurins), and is the process used for neurexin in the neurexin trans-synaptic adhesion module. Proposed replacements: synaptic membrane adhesion Supporting Evidence: PMID:18923512 Neurexins and neuroligins are synaptic cell-adhesion molecules that connect presynaptic and postsynaptic neurons at synapses, mediate signalling across the synapse, and shape the properties of neural networks by specifying synaptic functions PMID:16242404 neuroligin binding to alpha- and beta-neurexins mediates trans-synaptic cell adhesion but has distinct effects on synapse formation PMID:20064387 Binding of neurexins to LRRTM2 can produce cell-adhesion junctions, consistent with a trans-interaction regulated by neurexin alternative splicing |
| GO:0007165 signal transduction | IBA GO_REF:0000033 | MODIFY | Summary: IBA to the very general signal transduction, from a broad node (PTN002309037) spanning neurexins and related LNS/neurexin-like proteins. Reason: Neurexin signalling is trans-synaptic: neurexin-partner complexes spanning the cleft convey organizing signals in both directions (neurexin induces postsynaptic differentiation, postsynaptic ligands induce presynaptic differentiation via neurexin). Beyond synapse organization, the neurexin-1 SS4+ - cerebellin-2 - GluD1 complex controls postsynaptic NMDA receptor responses without changing synapse number, and mouse Nrxn1 carries GO:0099557 by IDA from that study. The informative term is therefore GO:0099557 trans-synaptic signaling by trans-synaptic complex, modulating synaptic transmission (a child of GO:0099545, used for NRXN3 on the same evidence). Generic signal transduction implies an intracellular cascade that is not established for neurexin. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN002309037 SUPPORTS TRANSFER Broad node spanning neurexins and related LNS/neurexin-like proteins; the signalling claim is inherited correctly, but at a generic level that hides the trans-synaptic nature of neurexin signalling. Proposed replacements: trans-synaptic signaling by trans-synaptic complex, modulating synaptic transmission Supporting Evidence: PMID:34135511 binding of presynaptic neurexin-cerebellin complexes to postsynaptic GluD1 controls glutamate receptor activity without affecting synapse numbers PMID:18923512 Neurexins and neuroligins are synaptic cell-adhesion molecules that connect presynaptic and postsynaptic neurons at synapses, mediate signalling across the synapse, and shape the properties of neural networks by specifying synaptic functions PMID:15620359 We show here that neurexin alone is sufficient to induce glutamate postsynaptic differentiation in contacting dendrites. PMID:20064388 LRRTM2 binds to both Neurexin 1alpha and Neurexin 1beta, and shRNA-mediated knockdown of Neurexin1 abrogates LRRTM2-induced presynaptic differentiation. |
| GO:0007268 chemical synaptic transmission | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Nrxn1 (IGI in alpha-neurexin multiple knockouts). Alpha-neurexins are required for normal Ca2+-triggered transmitter release, and Nrxn1-alpha single knockout reduces excitatory transmission. Reason: True, but broad: NRXN1 contributes to transmission by organizing the presynaptic release site (coupling Ca2+ channels to the release machinery) and by trans-synaptic effects on postsynaptic receptors. The core release role is captured by GO:0099171 presynaptic modulation of chemical synaptic transmission; this general parent is retained as non-core. Supporting Evidence: PMID:12827191 Using triple-knockout mice, we show that alpha-neurexins are not required for synapse formation, but are essential for Ca2+-triggered neurotransmitter release. PMID:19822762 Hippocampal slice physiology uncovered a defect in excitatory synaptic strength in neurexin-1alpha deficient mice, as revealed by a decrease in miniature excitatory postsynaptic current (EPSC) frequency and in the input-output relation of evoked postsynaptic potentials. |
| GO:0007269 neurotransmitter secretion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Nrxn1 (IGI in alpha-neurexin multiple knockouts): alpha-neurexins are essential for Ca2+-triggered neurotransmitter release. Reason: Alpha-neurexin triple knockout severely impairs Ca2+-triggered release without abolishing synapse formation, because synaptic Ca2+ channel function is reduced; alpha-neurexins likewise support Ca2+-triggered exocytosis in endocrine cells. The proposed mechanism is that alpha-neurexins organize the presynaptic terminal by coupling Ca2+ channels to the release machinery, i.e. NRXN1 contributes structure to the release site. Nrxn1-alpha single knockouts show a presynaptic excitatory phenotype, consistent with NRXN1 contributing to this function. Kept as non-core for consistency with NRXN2 and NRXN3, because neurexins tune release rather than executing secretion; the core release role is captured by the NEW GO:0099171 presynaptic modulation of chemical synaptic transmission row. Supporting Evidence: PMID:12827191 Using triple-knockout mice, we show that alpha-neurexins are not required for synapse formation, but are essential for Ca2+-triggered neurotransmitter release. PMID:12827191 alpha-neurexins organize presynaptic terminals by functionally coupling Ca2+ channels to the presynaptic machinery PMID:17035546 Our data support a general and essential role for alpha-neurexins in Ca2+-triggered exocytosis that is similarly important for secretion from neurons and endocrine cells. PMID:19822762 This result extends previous studies showing that Ξ±-neurexin deletions produce a primarily presynaptic phenotype |
| GO:0007399 nervous system development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA to nervous system development from the broad neurexin/neurexin-like node PTN000804946; includes NRXN1 itself among the sources. Reason: Not wrong - NRXN1 is neuron-specific and loss causes a neurodevelopmental disorder - but very general. The specific developmental contribution of neurexins is synapse organization/specification, captured by the synapse assembly and trans-synaptic signaling terms. Supporting Evidence: PMID:18057082 These findings suggest that neurexin1alpha function in correct dosage is necessary for normal neurological development. PMID:15620359 the neurexin-neuroligin link is a core component mediating both GABAergic and glutamatergic synaptogenesis |
| GO:0007411 axon guidance | TAS PMID:1621094 Neurexins: synaptic cell surface proteins related to the alp... | REMOVE | Summary: TAS from the 1992 neurexin discovery paper. Reason: The paper only notes that neurexin LNS repeats resemble sequences in laminin, slit and agrin, proteins implicated in axon guidance, and speculates that neurexins act as cell-recognition molecules at the nerve terminal. That is sequence similarity to other proteins, not evidence that NRXN1 functions in growth-cone guidance, and three decades of subsequent work place neurexin function at synapses rather than in axon pathfinding. Supporting Evidence: PMID:1621094 Neurexins contain single transmembrane regions and extracellular domains with repeated sequences similar to sequences in laminin A, slit, and agrin, proteins that have been implicated in axon guidance and synaptogenesis. PMID:18923512 Neurexins and neuroligins are synaptic cell-adhesion molecules that connect presynaptic and postsynaptic neurons at synapses, mediate signalling across the synapse, and shape the properties of neural networks by specifying synaptic functions |
| GO:0007416 synapse assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Nrxn1 (mouse IGI from alpha-neurexin knockouts and SynGO IDA/IMP). Reason: Neurexins participate in assembling synaptic contacts: neurexin alone induces glutamatergic and GABAergic postsynaptic differentiation in contacting dendrites, and neurexin is the presynaptic receptor through which neuroligins, LRRTM2 and cerebellin-GluD induce presynaptic differentiation. In vivo, however, alpha-neurexins are not required for synapse formation, and neurexin overexpression in neurons does not increase synapse density; neurexins act mainly as context-dependent specifiers of synapse properties. Retained as a genuine but non-core role. Supporting Evidence: PMID:15620359 We show here that neurexin alone is sufficient to induce glutamate postsynaptic differentiation in contacting dendrites. PMID:20064388 LRRTM2 binds to both Neurexin 1alpha and Neurexin 1beta, and shRNA-mediated knockdown of Neurexin1 abrogates LRRTM2-induced presynaptic differentiation. PMID:12827191 Using triple-knockout mice, we show that alpha-neurexins are not required for synapse formation, but are essential for Ca2+-triggered neurotransmitter release. PMID:20471353 when overexpressed in neurons, neurexins do not increase synapse density, but instead selectively suppressed GABAergic synaptic transmission without decreasing GABAergic synapse numbers |
| GO:0007612 learning | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA from the neurexin clade node PTN002227321 (sources include NRXN1/2/3 and the Drosophila neurexin). Reason: Loss of neurexin function alters learning-related behaviours across species, and biallelic NRXN1 loss causes severe intellectual disability in humans. This is an organism-level consequence of NRXN1's synaptic function rather than an activity it executes, so it is retained as non-core. Supporting Evidence: PMID:19896112 All four patients with recessive defects in CNTNAP2 or NRXN1 showed severe MR with lack of speech or with speech limited to single words (P1b), whereas motor milestones were normal or only mildly delayed, with a walking age of 2 years in P3. PMID:19822762 neurexin-1alpha deficient mice did not exhibit any obvious changes in social behaviors or in spatial learning |
| GO:0007612 learning | IMP PMID:19896112 CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Ho... | KEEP AS NON CORE | Summary: IMP from patients with compound-heterozygous NRXN1 deletion/stop mutation and severe intellectual disability (Pitt-Hopkins-like syndrome 2). Reason: Biallelic loss of NRXN1 gives fully penetrant severe intellectual disability, which supports a requirement for NRXN1 in cognitive development/learning. This is a downstream organism-level phenotype of a synaptic organizer; retained as non-core. Note that Nrxn1-alpha knockout mice show normal spatial learning and enhanced motor learning, so 'learning' is not a uniformly impaired readout. Supporting Evidence: PMID:19896112 All four patients with recessive defects in CNTNAP2 or NRXN1 showed severe MR with lack of speech or with speech limited to single words (P1b), whereas motor milestones were normal or only mildly delayed, with a walking age of 2 years in P3. PMID:19896112 Subsequent sequencing of NRXN1 in this patient revealed a stop mutation in exon 15 on the second allele, which was inherited from the healthy father PMID:19822762 neurexin-1alpha deficient mice did not exhibit any obvious changes in social behaviors or in spatial learning |
| GO:0009986 cell surface | IDA PMID:21424692 Truncating mutations in NRXN2 and NRXN1 in autism spectrum d... | ACCEPT | Summary: IDA: wild-type Flag-tagged human neurexin-1-alpha is detected on the surface of unpermeabilised COS cells and along axons of cultured neurons. Reason: Direct experimental evidence for the human protein; consistent with its type I membrane topology. Supporting Evidence: PMID:21424692 Whereas wild-type Flag-neurexin-1Ξ± targeted efficiently to the cell surface, as detected by bright staining of unpermeabilized cells with Flag antibody, little or no insACGG mutant was detected on the cell surface PMID:21424692 Whereas wild-type Flag-neurexin-1Ξ± was detected on the neuron surface including along the entire axons of relatively immature neurons |
| GO:0030534 adult behavior | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA to adult behavior (neurexin clade node PTN002227321 for IBA; ARBA for IEA). Reason: Neurexin loss changes adult behaviour in mouse (increased grooming, impaired prepulse inhibition and nest building in Nrxn1-alpha knockouts) and in invertebrates. This is a downstream phenotype of synaptic dysfunction; retained as non-core. Supporting Evidence: PMID:19822762 Hippocampal slice physiology uncovered a defect in excitatory synaptic strength in neurexin-1alpha deficient mice, as revealed by a decrease in miniature excitatory postsynaptic current (EPSC) frequency and in the input-output relation of evoked postsynaptic potentials. PMID:19822762 neurexin-1alpha deficient mice did not exhibit any obvious changes in social behaviors or in spatial learning |
| GO:0030534 adult behavior | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA to adult behavior (neurexin clade node PTN002227321 for IBA; ARBA for IEA). Reason: Neurexin loss changes adult behaviour in mouse (increased grooming, impaired prepulse inhibition and nest building in Nrxn1-alpha knockouts) and in invertebrates. This is a downstream phenotype of synaptic dysfunction; retained as non-core. Supporting Evidence: PMID:19822762 Hippocampal slice physiology uncovered a defect in excitatory synaptic strength in neurexin-1alpha deficient mice, as revealed by a decrease in miniature excitatory postsynaptic current (EPSC) frequency and in the input-output relation of evoked postsynaptic potentials. PMID:19822762 neurexin-1alpha deficient mice did not exhibit any obvious changes in social behaviors or in spatial learning |
| GO:0030534 adult behavior | IMP PMID:19896112 CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Ho... | KEEP AS NON CORE | Summary: IMP from patients with biallelic NRXN1 defects and severe intellectual disability. Reason: The patients have a severe neurodevelopmental disorder (intellectual disability, absent speech, autistic features, stereotypies, breathing anomalies), so an organism-level requirement for NRXN1 in normal behaviour is supported. 'Adult behavior' is a vague term that adds little beyond the learning and social behaviour rows, and NRXN1 does not execute a function in behaviour per se; it is retained as a non-core downstream phenotype, consistent with the IBA and IEA rows. Supporting Evidence: PMID:19896112 All four patients with recessive defects in CNTNAP2 or NRXN1 showed severe MR with lack of speech or with speech limited to single words (P1b), whereas motor milestones were normal or only mildly delayed, with a walking age of 2 years in P3. PMID:19896112 Additional variable anomalies were cerebellar hypoplasia, autistic behavior, and stereotypic movements. |
| GO:0031965 nuclear membrane | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS (nuclear membrane) from mouse Nrxn1; reflects biosynthetic/transit pools of a neuronal type I membrane protein rather than a site of action. Reason: The ISS source is mouse Nrxn1 (UniProtKB:Q9CS84), whose annotation to this term is an IDA from BHF-UCL (PMID:19036990, QuickGO 2026-11-06); an earlier version of this reason wrongly said mouse GOA had no experimental annotation. That paper studies epitope-tagged neurexins in cultured neurons and shows biosynthetic transit (PDZ-dependent ER/Golgi exit), so the donor evidence is transit, not residence, and the call is unchanged. Newly synthesised type I membrane proteins necessarily transit the ER/nuclear envelope and secretory vesicles, and neurexins assemble with partners during biosynthesis, but these are transit compartments, not where NRXN1 acts. NRXN1 functions at the presynaptic plasma membrane and active zone. Supporting Evidence: file:human/NRXN1/NRXN1-uniprot.txt SUBCELLULAR LOCATION: Presynaptic cell membrane PMID:1621094 An antibody to neurexin I showed highly concentrated immunoreactivity at the synapse. |
| GO:0031982 vesicle | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS (vesicle) from mouse Nrxn1; reflects biosynthetic/transit pools of a neuronal type I membrane protein rather than a site of action. Reason: The ISS source is mouse Nrxn1 (UniProtKB:Q9CS84), whose annotation to this term is an IDA from BHF-UCL (PMID:19036990, QuickGO 2026-11-06); an earlier version of this reason wrongly said mouse GOA had no experimental annotation. That paper studies epitope-tagged neurexins in cultured neurons and shows biosynthetic transit (PDZ-dependent ER/Golgi exit), so the donor evidence is transit, not residence, and the call is unchanged. Newly synthesised type I membrane proteins necessarily transit the ER/nuclear envelope and secretory vesicles, and neurexins assemble with partners during biosynthesis, but these are transit compartments, not where NRXN1 acts. NRXN1 functions at the presynaptic plasma membrane and active zone. Supporting Evidence: file:human/NRXN1/NRXN1-uniprot.txt SUBCELLULAR LOCATION: Presynaptic cell membrane PMID:1621094 An antibody to neurexin I showed highly concentrated immunoreactivity at the synapse. |
| GO:0033130 acetylcholine receptor binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Nrxn1, whose source is an IDA showing neurexin-1-beta forms complexes with alpha4beta2 nicotinic acetylcholine receptors. Reason: Neurexin-1-beta and alpha4beta2 AChRs form complexes in heterologous cells and co-immunoprecipitate from brain, and neurexin-1-beta targets these receptors to presynaptic terminals. The evidence is from the beta isoform (the shared LNS6/stalk/tail region is present in alpha isoforms), from a single study, and the interaction has not been shown to be direct with purified proteins. Retained as a non-core binding activity. Supporting Evidence: PMID:19567877 In non-neuronal tsA 201 cells, recombinant neurexin-1beta and mature alpha4beta2 AChRs form complexes. PMID:19567877 alpha4beta2 AChRs and neurexin-1beta also coimmunoprecipitate from rat brain lysates PMID:19567877 Collectively, these data suggest that neurexin-1beta targets alpha4beta2 AChRs to presynaptic terminals, which mature by trans-synaptic interactions between neurexins and neuroligins. |
| GO:0035176 social behavior | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA IEA to social behavior. Reason: Heterozygous and biallelic NRXN1 defects are associated with autistic features in humans, supporting an organism-level involvement; but Nrxn1-alpha knockout mice show no social deficits, and this is a downstream phenotype rather than a function NRXN1 executes. Non-core. Supporting Evidence: PMID:19896112 Additional variable anomalies were cerebellar hypoplasia, autistic behavior, and stereotypic movements. PMID:19822762 neurexin-1alpha deficient mice did not exhibit any obvious changes in social behaviors or in spatial learning |
| GO:0035176 social behavior | IMP PMID:18057082 A patient with vertebral, cognitive and behavioural abnormal... | KEEP AS NON CORE | Summary: IMP from a single case report of a de novo heterozygous deletion removing the NRXN1-alpha promoter and first coding exons, in a patient with mild intellectual disability and autistic features. Reason: A single heterozygous patient with multiple additional anomalies (vertebral malformations, dysmorphism) is weak evidence on its own, heterozygous NRXN1 deletions are incompletely penetrant, and Nrxn1-alpha knockout mice show normal social behaviour across four paradigms. Taken together with the biallelic-loss patients (PMID:19896112), an organism-level involvement in social behaviour is plausible, but it is a downstream phenotype of synaptic dysfunction rather than a function NRXN1 executes; retained as non-core. Supporting Evidence: PMID:18057082 The authors report a patient with mild mental retardation, autistic features, multiple vertebral malformations, and an unusual facial appearance who carries a de novo submicroscopic deletion of chromosome 2p16.3. PMID:19822762 neurexin-1alpha deficient mice did not exhibit any obvious changes in social behaviors or in spatial learning |
| GO:0035176 social behavior | IMP PMID:19896112 CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Ho... | KEEP AS NON CORE | Summary: IMP from patients with biallelic NRXN1 defects showing autistic behaviour among other features. Reason: Biallelic NRXN1 loss gives a severe neurodevelopmental disorder that includes autistic behaviour, so an organism-level requirement is supported. It is a downstream consequence of synaptic dysfunction; retained as non-core. Supporting Evidence: PMID:19896112 Additional variable anomalies were cerebellar hypoplasia, autistic behavior, and stereotypic movements. PMID:19896112 All four patients with recessive defects in CNTNAP2 or NRXN1 showed severe MR with lack of speech or with speech limited to single words (P1b), whereas motor milestones were normal or only mildly delayed, with a walking age of 2 years in P3. |
| GO:0038023 signaling receptor activity | TAS PMID:1621094 Neurexins: synaptic cell surface proteins related to the alp... | KEEP AS NON CORE | Summary: TAS from the neurexin discovery paper; neurexin-1-alpha was identified as the alpha-latrotoxin receptor. Reason: Neurexins are receptors for alpha-latrotoxin and serve as presynaptic receptors for postsynaptic organizers (neuroligins, LRRTMs), so a receptor label is defensible. The endogenous signalling mechanism downstream of neurexin is undefined, and the core activity is better captured as cell-cell adhesion mediator activity; non-core. Supporting Evidence: PMID:1621094 The neurexins were discovered by the identification of one member of the family as the receptor for alpha-latrotoxin. PMID:20064387 two unrelated postsynaptic cell-adhesion molecules, LRRTMs and neuroligins, unexpectedly bind to neurexins as the same presynaptic receptor PMID:10892652 This activity can be inhibited by addition of a soluble version of beta-neurexin, a receptor for neuroligin. |
| GO:0042297 vocal learning | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA IEA (vocal learning), apparently generalized from the human patient-phenotype annotations. Reason: The only experimental support is clinical absence of speech in patients with severe intellectual disability, which does not show that NRXN1 acts in vocalization per se. The rule-based transfer inherits this over-interpretation. Supporting Evidence: PMID:19896112 All four patients with recessive defects in CNTNAP2 or NRXN1 showed severe MR with lack of speech or with speech limited to single words (P1b), whereas motor milestones were normal or only mildly delayed, with a walking age of 2 years in P3. |
| GO:0042297 vocal learning | IMP PMID:19896112 CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Ho... | MARK AS OVER ANNOTATED | Summary: IMP (vocal learning) based on absent or single-word speech in patients with biallelic NRXN1 defects. Reason: Absent speech in these patients is a component of severe global intellectual disability, not evidence that NRXN1 functions specifically in producing or learning vocalizations. The learning and social behaviour rows already capture the organism-level phenotype; this is an over-interpretation of a clinical feature. Supporting Evidence: PMID:19896112 All four patients with recessive defects in CNTNAP2 or NRXN1 showed severe MR with lack of speech or with speech limited to single words (P1b), whereas motor milestones were normal or only mildly delayed, with a walking age of 2 years in P3. |
| GO:0042734 presynaptic membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA: presynaptic membrane. Reason: Neurexins are presynaptic type I membrane proteins concentrated at synapses and forming trans-synaptic complexes with postsynaptic partners; this is the principal site of action of NRXN1. Supporting Evidence: file:human/NRXN1/NRXN1-uniprot.txt SUBCELLULAR LOCATION: Presynaptic cell membrane PMID:1621094 An antibody to neurexin I showed highly concentrated immunoreactivity at the synapse. PMID:20064387 two unrelated postsynaptic cell-adhesion molecules, LRRTMs and neuroligins, unexpectedly bind to neurexins as the same presynaptic receptor |
| GO:0042734 presynaptic membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ISS: presynaptic membrane. Reason: Neurexins are presynaptic type I membrane proteins concentrated at synapses and forming trans-synaptic complexes with postsynaptic partners; this is the principal site of action of NRXN1. Supporting Evidence: file:human/NRXN1/NRXN1-uniprot.txt SUBCELLULAR LOCATION: Presynaptic cell membrane PMID:1621094 An antibody to neurexin I showed highly concentrated immunoreactivity at the synapse. PMID:20064387 two unrelated postsynaptic cell-adhesion molecules, LRRTMs and neuroligins, unexpectedly bind to neurexins as the same presynaptic receptor |
| GO:0043025 neuronal cell body | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS (neuronal cell body) from mouse Nrxn1; reflects biosynthetic/transit pools of a neuronal type I membrane protein rather than a site of action. Reason: The ISS source is mouse Nrxn1 (UniProtKB:Q9CS84), whose annotation to this term is an IDA from BHF-UCL (PMID:19036990, QuickGO 2026-11-06); an earlier version of this reason wrongly said mouse GOA had no experimental annotation. That paper studies epitope-tagged neurexins in cultured neurons and shows biosynthetic transit (PDZ-dependent ER/Golgi exit), so the donor evidence is transit, not residence, and the call is unchanged. Newly synthesised type I membrane proteins necessarily transit the ER/nuclear envelope and secretory vesicles, and neurexins assemble with partners during biosynthesis, but these are transit compartments, not where NRXN1 acts. NRXN1 functions at the presynaptic plasma membrane and active zone. Supporting Evidence: file:human/NRXN1/NRXN1-uniprot.txt SUBCELLULAR LOCATION: Presynaptic cell membrane PMID:1621094 An antibody to neurexin I showed highly concentrated immunoreactivity at the synapse. |
| GO:0048787 presynaptic active zone membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from the neurexin clade node PTN002227321: presynaptic active zone membrane. Reason: Consistent with neurexin function: alpha-neurexins organize the release site by coupling Ca2+ channels to the release machinery, and neurexins bind active-zone-associated PDZ scaffolds (CASK, Mints). Mouse Nrxn1 has SynGO IDA/IMP support for this location. Supporting Evidence: PMID:12827191 alpha-neurexins organize presynaptic terminals by functionally coupling Ca2+ channels to the presynaptic machinery PMID:12827191 link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins |
| GO:0050839 cell adhesion molecule binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse Nrxn1: binding of cell adhesion molecules. Reason: NRXN1 binds a series of postsynaptic or cleft adhesion molecules: neuroligins, LRRTMs, latrophilin/CIRL, and dystroglycan, in Ca2+-dependent and SS4-regulated interactions. The mouse source is an IPI showing neurexin-1-alpha binding NLGN2 and LRRTM2. Supporting Evidence: PMID:21424692 Neurexin-1Ξ± insACGG mutant expressed in COS cells failed to bind partners that bind with high affinity to wild-type neurexin-1Ξ±, the ectodomain of LRRTM2 fused to alkaline phosphatase (LRRTM2-AP; Fig. 2g) and the ectodomain of NLGN2 fused to immunoglobulin constant region (NLGN2-Fc; Fig. 2h). PMID:20064387 whereas neuroligins bind neurexins containing or lacking an insert in splice site #4, LRRTM2 only binds neurexins lacking an insert in splice site #4 PMID:22262843 neurexins lacking an insert at SS4 bind to CL1 with nanomolar affinity, whereas neurexins containing an insert at SS4 are unable to bind PMID:11470830 Dystroglycan binds specifically to a subset of the LNS domains of neurexins in a tight interaction that requires glycosylation of dystroglycan and is regulated by alternative splicing of neurexins. file:human/NRXN1/NRXN1-deep-research-falcon.md Alternative splicing at splice site 4 (SS4) is particularly critical for determining ligand-binding specificity and synaptic function |
| GO:0050885 neuromuscular process controlling balance | IMP NOT PMID:19896112 CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Ho... | ACCEPT | Summary: NOT annotation: patients with biallelic NRXN1 defects had normal or only mildly delayed motor milestones, which the curator read as absence of a role in balance. Reason: We agree that there is no evidence that NRXN1 functions in a neuromuscular process controlling balance: the patients' motor milestones were normal or only mildly delayed, and Nrxn1-alpha knockout mice have normal motor coordination (indeed enhanced rotarod learning). The negative statement is accepted. Supporting Evidence: PMID:19896112 All four patients with recessive defects in CNTNAP2 or NRXN1 showed severe MR with lack of speech or with speech limited to single words (P1b), whereas motor milestones were normal or only mildly delayed, with a walking age of 2 years in P3. PMID:19822762 Neurexin-1Ξ± KO mice displayed normal motor coordination during the initial trials, but exhibited enhanced motor learning compared with WT mice as the trials continued |
| GO:0050885 neuromuscular process controlling balance | ISS PMID:19822762 Mouse neurexin-1alpha deletion causes correlated electrophys... | REMOVE | Summary: ISS from mouse Nrxn1 (acts_upstream_of IMP, PMID:19822762) based on rotarod performance of Nrxn1-alpha knockout mice. Reason: The knockout mice showed normal motor coordination and improved rotarod performance over trials, which the authors interpret as enhanced motor learning, not altered balance control. Transferring this as a positive role in balance is not supported, and it directly contradicts the curated human NOT annotation for the same term. Supporting Evidence: PMID:19822762 Neurexin-1Ξ± KO mice displayed normal motor coordination during the initial trials, but exhibited enhanced motor learning compared with WT mice as the trials continued |
| GO:0051965 positive regulation of synapse assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Nrxn1 (IGI with Cbln1/Cbln2 in cortical synapse induction). Reason: Neurexins mediate synapse induction by cerebellins, neuroligins and LRRTMs, and neurexin itself induces postsynaptic differentiation, so a positive role in synapse assembly is supported by gain-of-function and blocking assays. In vivo, alpha-neurexins are not required for synapse formation, so neurexins act as synapse specifiers more than as obligatory builders; non-core. Supporting Evidence: PMID:21356198 Cbln1 and Cbln2 showed robust binding activities to NRXN1Ξ± and three Ξ²-NRXNs PMID:15620359 We show here that neurexin alone is sufficient to induce glutamate postsynaptic differentiation in contacting dendrites. PMID:12827191 Using triple-knockout mice, we show that alpha-neurexins are not required for synapse formation, but are essential for Ca2+-triggered neurotransmitter release. |
| GO:0051968 positive regulation of synaptic transmission, glutamatergic | ISS PMID:19822762 Mouse neurexin-1alpha deletion causes correlated electrophys... | KEEP AS NON CORE | Summary: ISS from mouse Nrxn1 IMP: Nrxn1-alpha knockout reduces mEPSC frequency and evoked excitatory synaptic strength in hippocampus. Reason: The phenotype is real and specific to excitatory transmission, and appears presynaptic. It reflects NRXN1's organizer role at excitatory synapses rather than a distinct regulatory activity; retained as non-core. Supporting Evidence: PMID:19822762 Hippocampal slice physiology uncovered a defect in excitatory synaptic strength in neurexin-1alpha deficient mice, as revealed by a decrease in miniature excitatory postsynaptic current (EPSC) frequency and in the input-output relation of evoked postsynaptic potentials. PMID:19822762 we detected no abnormality in neurexin-1Ξ± KO mice, suggesting that the impairment in synaptic strength is not due to a postsynaptic receptor-dependent mechanism |
| GO:0071625 vocalization behavior | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA IEA (vocalization behavior), apparently generalized from the human patient-phenotype annotations. Reason: The only experimental support is clinical absence of speech in patients with severe intellectual disability, which does not show that NRXN1 acts in vocalization per se. The rule-based transfer inherits this over-interpretation. Supporting Evidence: PMID:19896112 All four patients with recessive defects in CNTNAP2 or NRXN1 showed severe MR with lack of speech or with speech limited to single words (P1b), whereas motor milestones were normal or only mildly delayed, with a walking age of 2 years in P3. |
| GO:0071625 vocalization behavior | IMP PMID:18057082 A patient with vertebral, cognitive and behavioural abnormal... | MARK AS OVER ANNOTATED | Summary: IMP (vocalization behavior) from a single case report of a heterozygous de novo NRXN1-alpha deletion. Reason: The abstract describes mild intellectual disability and autistic features in one patient with additional congenital anomalies; this does not establish a specific role for NRXN1 in vocalization. Any speech impairment is part of global neurodevelopmental impairment. Supporting Evidence: PMID:18057082 The authors report a patient with mild mental retardation, autistic features, multiple vertebral malformations, and an unusual facial appearance who carries a de novo submicroscopic deletion of chromosome 2p16.3. PMID:18057082 These findings suggest that neurexin1alpha function in correct dosage is necessary for normal neurological development. |
| GO:0071625 vocalization behavior | IMP PMID:19896112 CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Ho... | MARK AS OVER ANNOTATED | Summary: IMP (vocalization behavior) based on absent or single-word speech in patients with biallelic NRXN1 defects. Reason: Absent speech in these patients is a component of severe global intellectual disability, not evidence that NRXN1 functions specifically in producing or learning vocalizations. The learning and social behaviour rows already capture the organism-level phenotype; this is an over-interpretation of a clinical feature. Supporting Evidence: PMID:19896112 All four patients with recessive defects in CNTNAP2 or NRXN1 showed severe MR with lack of speech or with speech limited to single words (P1b), whereas motor milestones were normal or only mildly delayed, with a walking age of 2 years in P3. |
| GO:0090129 positive regulation of synapse maturation | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS from mouse Nrxn1, whose source (IDA, PMID:19567877) is a study of neurexin-1-beta targeting alpha4beta2 nicotinic receptors to presynaptic terminals. Reason: The source study shows that neurexin-1-beta co-traffics alpha4beta2 AChRs to hemi-synapses in a coculture assay; it does not measure synapse maturation. Neurexin does contribute to synapse maturation more broadly, but this specific inference chain is weak and the term adds little over the synapse-organization annotations. Supporting Evidence: PMID:19567877 Collectively, these data suggest that neurexin-1beta targets alpha4beta2 AChRs to presynaptic terminals, which mature by trans-synaptic interactions between neurexins and neuroligins. |
| GO:0097104 postsynaptic membrane assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Nrxn1 (IDA, PMID:21424692): rodent neurexin-1-alpha expressed in COS cells clusters postsynaptic components in contacting dendrites. Reason: Neurexin-1-alpha presented on a heterologous cell induces clustering of LRRTM2, PSD-95, NLGN2 and gephyrin at dendritic contacts, i.e. it instructs postsynaptic membrane assembly in trans. This is a gain-of-function coculture readout of the trans-synaptic organizer role; non-core. Supporting Evidence: PMID:21424692 Whereas wild-type HA-neurexin1Ξ± induced robust clustering of glutamatergic postsynaptic components YFP-LRRTM2 and endogenous PSD-95 at dendrite contact sites PMID:21424692 whereas wild-type HA-neurexin1Ξ±-CFP induced clear clustering of GABAergic postsynaptic components endogenous NLGN2 and gephyrin at dendrite contact sites PMID:15620359 We show here that neurexin alone is sufficient to induce glutamate postsynaptic differentiation in contacting dendrites. |
| GO:0097109 neuroligin family protein binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: neuroligin family protein binding. Reason: Well established: alpha- and beta-neurexins bind all neuroligins through LNS6 in a Ca2+-dependent, splice-regulated (SS4 in neurexin, splice site B in neuroligin) interaction, forming a trans-synaptic adhesion complex. The IBA (node PTN002227321) is seeded by mouse, rat and bovine neurexin-1 experimental data and is well placed. Supporting Evidence: PMID:16242404 Unexpectedly, we now find that neuroligins also bind alpha-neurexins and that alpha- and beta-neurexin binding by neuroligin 1 is regulated by alternative splicing of neuroligin 1 (at splice site B) and of neurexins (at splice site 4). Reactome:R-HSA-6794346 alpha- and beta-neurexins both bind to all neuroligins to form cell adhesion complexes PMID:21424692 Neurexin-1Ξ± insACGG mutant expressed in COS cells failed to bind partners that bind with high affinity to wild-type neurexin-1Ξ±, the ectodomain of LRRTM2 fused to alkaline phosphatase (LRRTM2-AP; Fig. 2g) and the ectodomain of NLGN2 fused to immunoglobulin constant region (NLGN2-Fc; Fig. 2h). |
| GO:0097109 neuroligin family protein binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS: neuroligin family protein binding. Reason: Well established: alpha- and beta-neurexins bind all neuroligins through LNS6 in a Ca2+-dependent, splice-regulated (SS4 in neurexin, splice site B in neuroligin) interaction, forming a trans-synaptic adhesion complex. The IBA (node PTN002227321) is seeded by mouse, rat and bovine neurexin-1 experimental data and is well placed. Supporting Evidence: PMID:16242404 Unexpectedly, we now find that neuroligins also bind alpha-neurexins and that alpha- and beta-neurexin binding by neuroligin 1 is regulated by alternative splicing of neuroligin 1 (at splice site B) and of neurexins (at splice site 4). Reactome:R-HSA-6794346 alpha- and beta-neurexins both bind to all neuroligins to form cell adhesion complexes PMID:21424692 Neurexin-1Ξ± insACGG mutant expressed in COS cells failed to bind partners that bind with high affinity to wild-type neurexin-1Ξ±, the ectodomain of LRRTM2 fused to alkaline phosphatase (LRRTM2-AP; Fig. 2g) and the ectodomain of NLGN2 fused to immunoglobulin constant region (NLGN2-Fc; Fig. 2h). |
| GO:0097116 gephyrin clustering involved in postsynaptic density assembly | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA: gephyrin clustering involved in postsynaptic density assembly. Reason: Neurexin-1-alpha on a contacting cell induces clustering of NLGN2 and gephyrin in dendrites, through NLGN2 binding, and neurexin induces GABAergic postsynaptic differentiation. NRXN1 acts in trans as the organizing ligand; gephyrin clustering itself is executed by the postsynaptic neuroligin/collybistin machinery. Retained as a non-core description of the trans-synaptic organizer role. Supporting Evidence: PMID:21424692 whereas wild-type HA-neurexin1Ξ±-CFP induced clear clustering of GABAergic postsynaptic components endogenous NLGN2 and gephyrin at dendrite contact sites PMID:15620359 Surprisingly, neurexin also induces GABA postsynaptic differentiation. |
| GO:0097116 gephyrin clustering involved in postsynaptic density assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS: gephyrin clustering involved in postsynaptic density assembly. Reason: Neurexin-1-alpha on a contacting cell induces clustering of NLGN2 and gephyrin in dendrites, through NLGN2 binding, and neurexin induces GABAergic postsynaptic differentiation. NRXN1 acts in trans as the organizing ligand; gephyrin clustering itself is executed by the postsynaptic neuroligin/collybistin machinery. Retained as a non-core description of the trans-synaptic organizer role. Supporting Evidence: PMID:21424692 whereas wild-type HA-neurexin1Ξ±-CFP induced clear clustering of GABAergic postsynaptic components endogenous NLGN2 and gephyrin at dendrite contact sites PMID:15620359 Surprisingly, neurexin also induces GABA postsynaptic differentiation. |
| GO:0097118 neuroligin clustering involved in postsynaptic membrane assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Nrxn1 (IDA, PMID:21424692): neurexin-1-alpha clusters NLGN2 at dendritic contacts. Reason: Direct: neurexin binds neuroligins and clusters them at contact sites. A valid but gain-of-function coculture readout of the trans-synaptic organizer role; non-core. Supporting Evidence: PMID:21424692 whereas wild-type HA-neurexin1Ξ±-CFP induced clear clustering of GABAergic postsynaptic components endogenous NLGN2 and gephyrin at dendrite contact sites PMID:16242404 neuroligin binding to alpha- and beta-neurexins mediates trans-synaptic cell adhesion but has distinct effects on synapse formation |
| GO:0097119 postsynaptic density protein 95 clustering | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Nrxn1 (IDA, PMID:21424692): neurexin-1-alpha induces PSD-95 clustering at dendritic contacts. Reason: Neurexin-1-alpha induces clustering of glutamatergic postsynaptic components (LRRTM2, PSD-95) in trans, via its LRRTM/neuroligin ligands. Non-core description of the organizer role. Supporting Evidence: PMID:21424692 Whereas wild-type HA-neurexin1Ξ± induced robust clustering of glutamatergic postsynaptic components YFP-LRRTM2 and endogenous PSD-95 at dendrite contact sites PMID:15620359 We show here that neurexin alone is sufficient to induce glutamate postsynaptic differentiation in contacting dendrites. |
| GO:0098820 trans-synaptic protein complex | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from the neurexin clade node PTN002227321 (sources include NRXN1 itself): trans-synaptic protein complex. Reason: Core: NRXN1 forms cleft-spanning complexes with postsynaptic neuroligins and LRRTMs and, via cerebellin, with GluD receptors. This is the complex through which it mediates adhesion and trans-synaptic signalling. Supporting Evidence: PMID:18923512 Neurexins and neuroligins are synaptic cell-adhesion molecules that connect presynaptic and postsynaptic neurons at synapses, mediate signalling across the synapse, and shape the properties of neural networks by specifying synaptic functions PMID:16242404 neuroligin binding to alpha- and beta-neurexins mediates trans-synaptic cell adhesion but has distinct effects on synapse formation PMID:20537373 Here, we show that the N-terminal domain (NTD) of GluRdelta2 interacts with presynaptic neurexins (NRXNs) through cerebellin 1 precursor protein (Cbln1). |
| GO:2000463 positive regulation of excitatory postsynaptic potential | ISS PMID:19822762 Mouse neurexin-1alpha deletion causes correlated electrophys... | KEEP AS NON CORE | Summary: ISS from mouse Nrxn1 (PMID:19822762): reduced input-output relation of evoked field EPSPs in Nrxn1-alpha knockout hippocampus. Reason: Reflects the same presynaptic loss of excitatory synaptic strength as the glutamatergic-transmission row; the authors found no postsynaptic receptor-dependent mechanism. Retained as a non-core readout of NRXN1's synaptic role. Supporting Evidence: PMID:19822762 Hippocampal slice physiology uncovered a defect in excitatory synaptic strength in neurexin-1alpha deficient mice, as revealed by a decrease in miniature excitatory postsynaptic current (EPSC) frequency and in the input-output relation of evoked postsynaptic potentials. PMID:19822762 we detected no abnormality in neurexin-1Ξ± KO mice, suggesting that the impairment in synaptic strength is not due to a postsynaptic receptor-dependent mechanism |
| GO:0098632 cell-cell adhesion mediator activity | ISS PMID:20064387 LRRTM2 functions as a neurexin ligand in promoting excitator... | NEW | Summary: Neurexins bound to neuroligins, LRRTM2 or latrophilin-1 on an apposed cell form stable intercellular adhesion junctions; NRXN1 is the presynaptic adhesion partner in these trans-synaptic bridges. Reason: The core molecular activity of NRXN1 is to bind, from the presynaptic membrane, adhesion partners on the postsynaptic cell and thereby hold the two cells together - the definition of GO:0098632. Participation: NRXN1 itself is one half of the adhesive bond (cell aggregation assays with neurexin-expressing cells and LRRTM2-, neuroligin- or CL1-expressing cells). Comparator check: other synaptic and neuronal adhesion molecules in the same role (CLSTN1, contactins, LRRC4B/NGL-3 relatives, CD200) carry this term, and the repository's neurexin trans-synaptic adhesion module already uses it for neurexin. The existing cell adhesion molecule binding and neuroligin family protein binding rows describe the partner, not the adhesive activity. Evidence is from rodent neurexins (ISS), which are ~99% identical to human NRXN1. Supporting Evidence: PMID:20064387 Binding of neurexins to LRRTM2 can produce cell-adhesion junctions, consistent with a trans-interaction regulated by neurexin alternative splicing PMID:22262843 Cell adhesion assays using cells expressing neurexins and CL1 revealed that their interaction produces a stable intercellular adhesion complex, indicating that their interaction can be trans-cellular. PMID:16242404 neuroligin binding to alpha- and beta-neurexins mediates trans-synaptic cell adhesion but has distinct effects on synapse formation PMID:18923512 Neurexins and neuroligins are synaptic cell-adhesion molecules that connect presynaptic and postsynaptic neurons at synapses, mediate signalling across the synapse, and shape the properties of neural networks by specifying synaptic functions |
| GO:0099171 presynaptic modulation of chemical synaptic transmission | ISS PMID:19822762 Mouse neurexin-1alpha deletion causes correlated electrophys... | NEW | Summary: Nrxn1-alpha knockout mice have reduced spontaneous excitatory release at hippocampal synapses, and alpha-neurexins are required for Ca2+-triggered release by coupling Ca2+ channels to the release machinery. Reason: Captures the presynaptic release role at the right level, consistent with NRXN2 and NRXN3. Participation: NRXN1 resides in the presynaptic active zone membrane and contributes structure to the release site (Ca2+ channel coupling, PDZ scaffold binding); it tunes release rather than executing exocytosis, so a modulation term fits better than neurotransmitter secretion. Comparator check: mouse Nrxn2 and Nrxn3 carry GO:0099171 by IDA/IMP (SynGO), and the NRXN2 and NRXN3 reviews add it. Evidence is from mouse (ISS). Supporting Evidence: PMID:19822762 Hippocampal slice physiology uncovered a defect in excitatory synaptic strength in neurexin-1alpha deficient mice, as revealed by a decrease in miniature excitatory postsynaptic current (EPSC) frequency and in the input-output relation of evoked postsynaptic potentials. PMID:19822762 This result extends previous studies showing that Ξ±-neurexin deletions produce a primarily presynaptic phenotype PMID:12827191 alpha-neurexins organize presynaptic terminals by functionally coupling Ca2+ channels to the presynaptic machinery |
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Download this section (compressed HTML)Q: What presynaptic molecule(s) transduce ligand binding by neurexin into presynaptic differentiation and Ca2+ channel coupling? The cytoplasmic tail binds CASK and Mints, but it is not established that these interactions carry the signal, so whether neurexin is a signaling receptor in the GO sense remains open.
Q: This review uses GO:0099557 (trans-synaptic signaling modulating transmission) for NRXN1 and NRXN3, where cerebellin-GluD1 evidence shows receptor tuning without synapse loss, and its parent GO:0099545 for NRXN2, whose evidence is synapse organization. Should the postsynaptic partners (NLGN1-4, LRRTM1-4, CBLN1/2, GRID1/2) be annotated on the same split?
Q: Behaviour annotations (vocal learning, vocalization, adult behaviour, social behaviour) for NRXN1 derive from clinical features of patients with severe intellectual disability. Is there a curation convention for when patient phenotypes justify behaviour-process IMP annotations for a synaptic organizer?
Experiment: Cell aggregation assays using human NRXN1-alpha SS4+ and SS4- isoforms against cells expressing human LRRTM2, NLGN1 and ADGRL1, with Ca2+ chelation and LNS6 Ca2+-site mutants as controls.
Hypothesis: Human NRXN1-alpha, like rodent neurexins, mediates cell-cell adhesion with LRRTM2, NLGN1 and ADGRL1 in an SS4-dependent manner.
Type: cell aggregation assay
Experiment: Isogenic human iPSC-derived neurons with NRXN1-alpha-specific deletion versus pan-alpha-neurexin deletion; measure evoked release, presynaptic Ca2+ transients and release probability.
Hypothesis: NRXN1-alpha contributes to Ca2+ channel coupling at human synapses independently of NRXN2/3.
Type: electrophysiology in iPSC-derived neurons
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