Neuroligin-2 Mimetics Positively Modulate Beta Cells Functions

The β-cell membrane and the presynaptic active zones of neurons are the assembly sites of very similar protein complexes mediating regulated secretion. Cell-surface, synaptic proteins that mediate interactions between neurons and guide the formation and functional maturation of synapses have been recently identified. These synapse-inducing proteins include the neuroligins and their binding partners: the neurexins. Like other synaptic adhesion molecules, these participate in transcellular protein-protein interactions across the synaptic cleft. We have shown that β-cells express neuroligins and neurexins on their plasma membrane, among them neuroligin-2 (NL-2) and neurexin-1 (NX-1). We also have found that insulin secretion and the proliferation rate of β-cells increased when β -cells were co-cultured with cells overexpressing NL-2. Such co-cultured β-cells were also less vulnerable to both oxidative and ER stress.

Based on these results, we aim to design and synthesize potent and effective NL-2 mimetics that might lead to the development of a novel class of antidiabetic drugs. We created mimetic NL-2 (9-amino acid peptide derived from the NL-4 crystal structure) covered by hydrogel nanoparticles. We hypothesized that this cluster may enhance β-cell function, increasing glucose-stimulated insulin secretion and functional maturity and protecting β-cells in stress conditions. Indeed, clustered peptide which was derived from NL-2 sequence increased β-cells cell proliferation and protected them from oxidative stress. Furthermore, such cluster might support β-cells differentiation from stem cells and their viability in vitro which might increase the survival of further β-cells transplant. This application might be useful as a basis for development of novel antidiabetic treatment.