Neurexin

Neurexins are a family of presynaptic cell-adhesion molecules encoded by NRXN1, NRXN2, and NRXN3. They contribute to the formation, specification, and functioning of synapses by forming trans-synaptic complexes with a variety of postsynaptic ligands, most notably neuroligins, but also LRRTMs and cerebellins (Cbln1) in combination with GluD receptors. Through these interactions, neurexins organize the molecular architecture of synapses and influence synapse maturation, specificity, and transmitter release.

Neurexins exist as multiple isoforms generated by alternative promoters and extensive alternative splicing. Alpha-neurexins are longer and carry more extracellular LNS (laminin/neurexin/sex-hint) domains and EGF-like repeats, whereas beta-neurexins are shorter and start at a later portion of the extracellular region. All isoforms are single-pass transmembrane proteins with a short intracellular tail that can bind scaffolding proteins such as CASK via a PDZ-binding motif, linking the synaptic adhesion complex to the cytoskeleton and signaling machinery. The extracellular region contains several LNS and EGF-like domains, enabling diverse ligand interactions.

Alternative splicing at multiple sites (commonly referred to as splice sites SS1–SS6) modulates ligand-binding properties, influencing affinity for neuroligins and other partners. Expression of neurexins is widespread in the CNS with development- and region-specific patterns, reflecting their roles in synapse formation and plasticity.

Genetic variation in NRXN genes, including copy-number variants and point mutations, has been associated with neurodevelopmental disorders such as autism spectrum disorder, schizophrenia, and epilepsy. Animal models show altered synapse number, balance of excitation and inhibition, and behavioral deficits when neurexin function is disrupted.