THE MAKING OF NEUREXINS

Neurexins are neuronal cell-surface proteins with up to thousands of i soforms. These isoforms are generated by alternative splicing of trans cripts from six promoters in three genes. The structure of neurexins r esembles cell-surface receptors with a modular architecture suggestive of a sequential assembly during evolution. Neurexins probably perform multiple functions in the brain. They participate in intercellular ju nctions in which beta-neurexins lightly bind to a second class of neur onal cell-surface receptors called neuroligins. Intracellularly, the n eurexin/neuroligin junction is bound by CASK on the neurexin side and PSD95 on the neuroligin side. CASK and PSD95 are homologous membrane-a ssociated guanylate kinases that bind to the neurexin/neuroligin junct ion via PDZ domains, creating an asymmetric junction (neurexin/neuroli gin) with similar intracellular binding partners. In addition to a fun ction as cell-adhesion molecules, neurexins may also serve as a signal ling receptor, because a class of ligands for alpha-neurexins called n eurexophilins is similar to peptide hormones. Finally, at least one ne urexin isoform, neurexin I alpha, represents a high-affinity receptor for alpha-latrotoxin, which is a potent excitatory neurotoxin. Thus, n eurexins constitute a large family of neuronal receptors that may be i nvolved in multiple interactive functions between neurons.