Structure of neurexins and neuroligins. In humans, there are three neurexin genes and five neuroligin genes. Each neurexin gene uses an upstream promoter to generate the larger α-neurexins and a downstream promoter to generate the smaller β-neurexins. Thus, β-neurexins can be thought of as N-terminally truncated α-neurexins that have a short β-specific leader (βN). In α-neurexins, the LNS (laminin, neurexin, sex-hormone-binding protein) domains are organized with EGF (epidermal growth-factor)-like domains into three homologous modules, I–III. The position of each of five sites of alternative splicing (SS1–SS5) is indicated. Neuroligins contain an extracellular acetylcholinesterase (AChE)-homologous domain that contains one or two sites of alternative splicing (SSA, plus SSB in the case of neuroligin 1). Both neurexins and neuroligins contain a highly glycosylated region (CH) and a transmembrane domain (TM; not present in some splice variants of neurexin 3), and terminate in PDZ-domain-binding sites (PDZ BD). Shown between the neurexins and neuroligins are structures of AChE, a model for the AChE-homologous domain of neuroligins, and the neurexin 1β LNS domain [7]. The position of splice sites SS2–SS4 is shown on a single LNS domain for simplicity, although SS2 and SS3 actually occur in different LNS domains of α-neurexins. Note also that the left face of the neurexin LNS as shown here binds neuroligin [9••] but the precise structure and interacting region of neuroligin has not been reported yet. The structure files E.C.3.1.1.7 (AChE) and d1c4ra (neurexin LNS) were downloaded from the Research Collaboratory for Structural Bioinformatics protein data bank (http://www.rcsb.org/pdb/home/home.do) and visualized using the program Visual Molecular Dynamics [66].

Molecular interactions at glutamatergic and GABAergic synapses that are linked by neurexins and neuroligins. (a) A glutamatergic synapse. (b) A GABAergic synapse. The broken lines between neuroligin 2 and GABA receptors (GABAR) and Gephyrin indicate that there are some links (direct or indirect) but their nature is not yet known. At glutamatergic synapses, α-neurexins can bind neuroligin 1 that lacks an insert at the B splice site (−B) but the majority of neuroligin 1 is in the +B form, which does not bind to α-neurexins. Additional abbreviations: AMPAR, AMPA receptor; NMDAR, NMDA receptors; VGAT, vesicular GABA transporter; VGlut1, vesicular glutamate transporter.