Neurexins (NRXN) are a family of presynaptic cell adhesion proteins that have roles in connecting neurons at the synapse. They are located mostly on the presynaptic membrane and contain a single transmembrane domain. The extracellular domain interacts with proteins in the synaptic cleft, most notably neuroligin, while the intracellular cytoplasmic portion interacts with proteins associated with exocytosis. Neurexin and neuroligin "shake hands," resulting in the connection between the two neurons and the production of a synapse. Neurexins mediate signaling across the synapse, and influence the properties of neural networks by synapse specificity. Neurexins were discovered as receptors for α-latrotoxin, a vertebrate-specific toxin in black widow spider venom that binds to presynaptic receptors and induces massive neurotransmitter release. In humans, alterations in genes encoding neurexins are implicated in autism and other cognitive diseases, such as Tourette syndrome and schizophrenia. Structure In mammals, neurexin is encoded by three different genes (NRXN1, NRXN2, and NRXN3) each controlled by two different promoters, an upstream alpha (α) and a downstream beta (β), resulting in alpha-neurexins 1-3 (α-neurexins 1-3) and beta-neurexins 1-3 (β-neurexins 1-3). In addition, there are alternative splicing at 5 sites in α-neurexin and 2 in β-neurexin; more than 2000 splice variants are possible, suggesting its role in determining synapse specificity. The encoded proteins are structurally similar to laminin, slit, and agrin, other proteins involved in axon guidance and synaptogenesis. α-Neurexins and β-neurexins have identical intracellular domains but different extracellular domains. The extracellular domain of α-neurexin is composed of three neurexin repeats which each contain LNS (laminin, neurexin, sex-hormone binding globulin) – EGF (epidermal growth factor) – LNS domains. N1α binds to a variety of ligands including neuroligins and GABA receptors, though neurons of every receptor type express neurexins. β-Neurexins are shorter versions of α-neurexins, containing only one LNS domain. β-Neurexins (located presynaptically) act as receptors for neuroligin (located postsynaptically). Additionally, β-Neurexin has also been found to play a role in angiogenesis. The C terminus of the short intracellular section of both types of neurexins binds to synaptotagmin and to the PDZ (postsynaptic density (PSD)-95/discs large/zona-occludens-1) domains of CASK and Mint. These interactions form connections between intracellular synaptic vesicles and fusion proteins. Thus neurexins play an important role in assembling presynaptic and postsynaptic machinery. Trans-synapse, the extracellular LNS domains have a functional region, the hyper-variable surface, formed by loops carrying 3 splice inserts. This region surrounds a coordinated Ca2+ ion and is the site