Neuroligin 2/NLGN2: Proteins and Enzymes

Neuroligin 2 (NLGN2) is one of several type I transmembrane Neuroligins that are expressed on neuronal postsynaptic densities. Neuroligins play an important role in synaptic development and function. Mature human Neuroligin 2 is a 105 kDa protein that consists of a 663 amino acid (aa) extracellular domain (ECD) with a catalytically inactive cholinesterase-like domain, a 21 aa transmembrane segment, and a 137 aa cytoplasmic tail. Within the ECD, human Neuroligin 2 shares 98% aa sequence identity with mouse and rat Neuroligin 2. Alternate splicing generates an isoform with a 17 aa insertion at splice site A within the ECD. This recombinant protein does not contain the splice site A insert (-SS A). Neuroligin 2 is expressed on neurons in the brain and also on pancreatic beta cells where it facilitates insulin secretion. The -SS A isoform is uniformly expressed among inhibitory and excitatory synapses, while the +SS A isoform is enriched at inhibitory GABAergic synapses. Neuroligin 2 clusters at postsynaptic densities in association with other postsynaptic proteins including S-SCAM, PSD-95, gephyrin, and Neuroligin 3. Synaptic maturation is promoted by the binding of Neuroligin 2 with presynaptic Neurexins, and these interactions are restricted to particular combinations of isoforms of the binding partners. Neuroligin 2 interacts with the alpha and beta forms of Neurexin 1, 2, and 3. Its -SS A and +SS A isoforms are bound equally well by Neurexin 1 beta isoforms (-SS4 or +SS4), although only the Neurexin 1 beta +SS4 isoform can induce development of Neuroligin 2-dependent GABAergic contacts.