Background:The cell surface, transmembrane protein neurexin may play a role in insulin secretion. Results: Knockdown and knock-out of neurexin-1␣, the predominant ␤-cell isoform, increased insulin secretion and impaired secretory granule docking. Conclusion: Neurexin-1␣ helps mediate insulin granule docking and thereby constrains secretion. Significance: Neurexin-1␣ could couple localization and functioning of the insulin docking and secretory machinery to extracellular protein interactions.