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NEUREXIN
=Intro= Neurexins are neuronal proteins involved in cell recognition, specifically synaptic adhesion. 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 plays an important role in synapse formation, and could even account for one mechanism of synapse specificity.

=Structure= In mammals, neurexin is encoded by 3 different genes (NRXN1, 2, and 3) controlled by 2 different promoters (upstream α and downstream β) resulting in α-neurexins 1-3 and β-neurexins 1-3. They are structurally similar to laminin, slit, and agrin, other proteins involved in axon guidance and synaptogenesis. The extracellular domain of α-neurexin is composed of three neurexin repeats which each contain LNS (laminin, nectin, 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. With 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.

α-Neurexins and β-neurexins have identical intracellular domains but different extracellular domains. 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 of neuroligin binding.

=Neurexin-Neuroligin Binding= The different combinations of neurexin to neuroligin, and alternative splicing of neuroligin and neurexin genes, control binding between neuroligins and neurexins, adding to synapse specificity. Neurexins alone are capable of recruiting neuroligins in postsynaptic cells to a dendritic surface, resulting in clustered neurotransmitter receptors and other postsynaptic proteins and machinery. Their neuroligin partners can induce presynaptic terminals by recruiting neurexins. Synapse formation can therefore be triggered in either direction by these proteins. Neuroligins and neurexins can also regulate formation of glutamatergic (excitatory) synapses, and GABAergic (inhibitory) contacts using a neuroligin link. Regulating these contacts suggests neurexin-neuroligin binding could balance synaptic input.

=Other Species= Homologues of α-neurexin have also been found in several invertebrate species including Drosophila, Caenorhabditis elegans, honeybees and Aplysia (N and N). In Drosophila melanogaster, NRXN genes (only one α-neurexin) are critical in the assembly of glutamatergic neuromuscular junctions but are much simpler.