Neurexins (NRXNs) are a family of transmembrane, synaptic adhesion molecules. NRXNS were identified as receptors for α-latrotoxin, a presynaptic toxin that triggers massive neurotransmitter release¹. Neurexins are largely presynaptic proteins that form a trans-synaptic cell-adhesion complex with postsynaptic neuroligins². They are encoded by three genes (NRXN1, NRXN2 and NRXN3), each using an upstream promoter to produce the longer α-isoform (α-NRXNs) and a downstream promoter to generate a shorter β-isoform (β-NRXNs).

The α-isoforms and β-isoforms of each neurexin are single-pass transmembrane proteins maintaining identical transmembrane and intracellular domains but having distinct extracellular domains. NRXNs in neurons localize to the presynaptic membrane and bind trans-synaptically to postsynaptic adhesion molecules and receptors³. Neurexins are expressed in all neurons, and are subject to extensive alternative splicing, generating >1,000 splice variants, some of which exhibit highly regulated developmental and spatial expression patterns⁴.

The structure of α-Neurexins is composed of 6 LNS domains (laminin, neurexin, sex-hormone-binding protein domain) and 3 EGF-like domains. In the mammalian brain they are known to interact with neuroligins, dystroglycan and neurexophilins. Neurexin 3α splicing can give rise to secreted and transmembrane forms of the protein. The biological function of the secreted form remains unknown⁵.

Changes in Neurexin 3α are associated with autism, drug addiction and obesity⁶.