Neurexin 2, also known as NRXN2, is a neuronal type I transmembrane molecule that is encoded by one of three Neurexin genes (1, 2). Mature human Neurexin 2 alpha is an approximately 200 kDa N- and O‑glycosylated protein with a 1608 amino acid (aa) extracellular domain (ECD) and a 55 aa cytoplasmic domain. The ECD contains six LNS domains interspersed with three EGF-like domains and a juxtamembrane O‑glycosylation region (1 ‑ 3). The ECD of human Neurexin 2 alpha shares 98% and 99% aa sequence identity with mouse and rat Neurexin 2 alpha, respectively. Transcription of the Neurexin 2 gene from an internal promoter gives rise to Neurexin 2 beta which lacks the first five LNS domains and all of the EGF-like domains (3, 4). Human Neurexin 2 alpha is combinatorially spliced at five canonical sites in the ECD, giving rise to nearly 200 potential isoforms (4). This recombinant protein (isoform 2 according to SwissProt # Q9P2S2) does not contain inserts at splice sites 1, 2, 3,or 4. Neurexin 2 alpha is primarily expressed in the brain where it is localized to presynaptic terminals (3, 5, 6). It binds Neurexophilin 1 and 3, Neuroligin 2, and Dystroglycan (7 ‑ 9). Only Neurexin 2 isoforms that lack the insert at splice site 4 additionally bind LRRTM2 (10). The interaction between Neurexins and Neuroligins is complex and is restricted to particular combinations of splice forms of each binding partner (11). These interactions promote the differentiation and maintenance of postsynaptic GABA and NMDA but not AMPA terminals (8, 12). At presynaptic terminals as well as in pituitary melanotrophs, alpha Neurexins are required for coupling voltage-dependent calcium channel signaling to neurotransmitter or hormone release (13 ‑ 15).