NRXN2 (human, Q9P2S2) curation notes

2026-09-30 — initial review

Q9P2S2 is the canonical neurexin-2-alpha entry (1712 aa; signal peptide 1-28, six LNS/laminin G-like domains with three EGF repeats, TM helix 1637-1657, cytoplasmic tail 1658-1712). The beta isoforms from the internal promoter are a separate UniProt entry, P58401 (its GOA rows are in NRXN2-bioinformatics/NRXN2-beta-isoform-entry-goa.tsv, reference only, not reviewed).
UniProt Ca2+-binding residues by similarity in LNS2 (335, 352, 420), LNS4 (779, 796, 854), LNS6 (1189, 1206, 1288, 1290); heparan sulfate at Ser1400 [file:human/NRXN2/NRXN2-uniprot.txt "SUBCELLULAR LOCATION: Presynaptic cell membrane"].
Human GOA (38 rows) is almost entirely IBA/ISS/IEA/TAS; the only human experimental rows are IMP behaviour annotations from one family (PMID:21424692). Most ISS rows come from mouse Nrxn2 (E9Q7X7), whose sources are BHF-UCL IDA/IPI from PMID:21424692 and MGI IGI from PMID:12827191 (checked in QuickGO).
The Falcon deep-research report was used for retrieval only. It presents the "anti-synaptogenic" role as settled and does not mention the conflicting data or retractions (below).

Neurexin-2-alpha binds NLGN2 and LRRTM2 and clusters postsynaptic components; ASD truncation removes LNS6 and abolishes both PMID:21424692 PMID:21424692
IgSF21 is an NRXN2-alpha-selective ligand (LNS1), recruiting axonal NRXN2-alpha in trans to drive inhibitory presynaptic differentiation PMID:28864826 PMID:28864826 The same paper frames NRXN2-alpha as both receptor and ligand PMID:28864826
Adhesion: neurexin-2-beta cells aggregate with latrophilin-1 cells PMID:22262843; neurexin-2-beta Ca2+ site needed for neuroligin-1 adhesion PMID:20064387
Dystroglycan via LNS2 PMID:11470830
Overexpressed neurexin-2-beta suppresses GABAergic transmission PMID:20471353
Alpha-neurexins collectively required for release, not synapse formation PMID:12827191 PMID:17347997 But Nrxn2-alpha alone is dispensable in secretory cells PMID:17035546

Neocortex (Missler lab): PMID:25745399 PMID:25745399
Hippocampus (Sudhof lab): PMID:36608123 PMID:36608123
Lin 2023 explicitly disputes the Born 2015 mouse line ("the mouse line used in this paper was generated originally in our laboratory but found to not represent an Nrxn2 deletion"). The Nrxn2-alpha line (Missler 2003) was also used by Dachtler.
Integrity status (checked in PubMed, 2026-09-30):
PMID:36608123 (Lin 2023 Sci Adv): 2025 expression of concern; in March 2026 the EoC was removed and an erratum published (PMID:41824587), editors stating "the authors' original results are maintained". Cited, but reference marked DISPUTED.
PMID:36961922 (Lin et al. 2023 PNAS, "Neurexin-2 restricts synapse numbers and restrains the presynaptic release probability by an alternative splicing-dependent mechanism"): RETRACTED (PMID:38442183). Not fetched, not cited.
PMID:28472659 (Chen et al. 2017): retracted; not cited (as for NRXN1).
Behaviour: PMID:25423136 PMID:36941261 PMID:36941261 PMID:38702381 PMID:26595880
Human: one ASD boy with heterozygous NRXN2 frameshift, inherited from a father with language delay PMID:21424692

ACCEPT (12): plasma membrane (IBA + 4 Reactome TAS), presynaptic membrane (IEA, ISS), presynaptic active zone membrane IBA, trans-synaptic protein complex IBA, neuroligin family protein binding (IBA, ISS), cell adhesion molecule binding ISS.
MODIFY (4): neuron cell-cell adhesion (IEA, TAS) -> GO:0099560 synaptic membrane adhesion; signal transduction (IBA, ISS) -> GO:0099545 trans-synaptic signaling by trans-synaptic complex.
MARK_AS_OVER_ANNOTATED (5): calcium channel regulator activity ISS; vocal learning (IEA, IMP) and vocalization behavior (IEA, IMP).
KEEP_AS_NON_CORE (17): transmembrane signaling receptor activity (IBA, ISS); chemical synaptic transmission; neurotransmitter secretion; nervous system development; synapse assembly; learning; adult behavior x3; social behavior x2; postsynaptic membrane assembly; gephyrin clustering x2; neuroligin clustering; PSD-95 clustering.
NEW (2): GO:0098632 cell-cell adhesion mediator activity (ISS, PMID:22262843); GO:0099171 presynaptic modulation of chemical synaptic transmission (ISS, PMID:36608123). Comparator for 0099171: SynGO has mouse Nrxn2 (PMID:36608123) and mouse Nrxn3 (PMID:26030848) on this term; human NRXN1/NRXN3 do not carry it.

GO:0007269 neurotransmitter secretion: ACCEPT (core) for NRXN1, KEEP_AS_NON_CORE here. The IGI source is combined alpha-neurexin deletion; NRXN2 alone is dispensable in secretory cells and its release phenotype changes sign between neocortex and hippocampus. The direction-neutral GO:0099171 (NEW) is used as the core process instead.
Third core function: NRXN1 used PDZ domain binding (GO:0030165) + neurotransmitter secretion. NRXN2 has no protein-binding rows and no cached NRXN2-specific CASK/Mint evidence, so no PDZ MF is asserted; the core function is modulation of release/synapse number with no MF.
Synapse assembly kept non-core as for NRXN1, but the reason differs: NRXN2 both promotes (coculture, IgSF21) and restricts (hippocampus) synapse assembly.
Social behaviour kept non-core as for NRXN1, but mouse support is much stronger for NRXN2 (Nrxn1-alpha KOs are socially normal; Nrxn2-alpha KOs are not).
Core trans-synaptic organizer function adds the NRXN2-alpha-selective ligand IgSF21.