This

clustering is negatively modulated by up-stream neurexin sequences (Kang et al., 2008). A C-terminus binding motif Lumacaftor research buy is required for neurexin to leave the endoplasmic reticulum and for targeting to and insertion at synaptic plasma membranes. Neurexin is transported along the axon in vesicles that do not contain active zone precursor proteins, but which carry CASK (Calcium/calmodulin- dependent serine protein kinase), RIM1α (Regulating synaptic membrane exocytosis protein 1α) and calcium channels and possibly other elements of the transmitter release machinery (Fairless et al., 2008). Insertion of neurexin in the presynaptic plasma membrane is clearly important for binding essential components into the presynaptic release machinery. In addition, the interactions of neurexins with neuroligins promote

postsynaptic differentiation, presumably because they help to stabilise both proteins and thereby their pre- and postsynaptic binding partners. These interactions and the influence they have are affected by the splice variants present. For example, NL1 lacking an insert in splice site B binds both α and β neurexin and, if overexpressed, has a more powerful effect on synaptic size than on number, unlike the variant with the insert, which affects synapse number more powerfully (Boucard et al., 2005). These studies have led to the suggestion that the combination of neurexin and neuroligin isoforms that is expressed influences a wide range of synaptic properties. The many binding partners and extensive alternative splicing of neurexins, the conservation of splice Histone Methyltransferase inhibitor insert sequences

and positions across species, and the co-expression of several neurexin isoforms in single cells may suggest that they are mediators of synapse specificity and that Ferroptosis inhibitor this specificity is important. How different splice variants may be concentrated at different presynaptic terminals remains to be established, but a mechanism shared with that underlying the specific localisation of certain release machinery components seems likely. Neuroligins (NL1, NL2 and NL3) are the postsynaptic neurexin interactors. They exhibit less extensive alternative splicing, which occurs at their single LNS domain and at the AChE (acetylcholine esterase)-homologous regions, but important selectivity nevertheless (Kang et al., 2008). NL2 promotes formation of and is localised to GABAergic synapses (Varoqueaux et al., 2004), while NL1 promotes glutamateric synapse formation. NL3 aggregates at subsets of both glutamatergic and GABAergic synapses, forming complexes with NL1 or NL2 (Budreck & Scheiffele, 2007). Without NL2, GABAAR clusters do form in the plasma membranes of transfected HEK 293T cells co-cultured with neurones. However, the clusters that form are reported to be small, functionally silent and labile, and do not recruit the scaffolding protein gephyrin.