Role of complexin 2 in the regulation of hormone secretion from the islet of Langerhans

Regulated secretion of insulin from β-cells, glucagon from α-cells, and somatostatin from δ-cells is necessary for the maintenance of glucose homeostasis. The release of these hormones from pancreatic islets requires the assembly and disassembly of the SNARE protein complex to control vesicle fusion. Complexin 2 (Cplx 2) is a small soluble synaptic protein that participates in the priming and release of vesicles. It plays a dual role as a molecular switch that clamps and prevents fusion pore opening, which subsequently undergoes a conformational change upon Ca²⁺ binding to synaptotagmin to facilitate exocytosis. Using a Cplx 2 knockout (KO) mouse model, we show a direct inhibitory role of Cplx 2 for glucagon and somatostatin secretion, along with an indirect role in the paracrine inhibition of insulin secretion by somatostatin. Deletion of Cplx 2 increases glucagon and somatostatin secretion from intact mouse islets, whereas there is no effect on insulin secretion. The normal paracrine inhibition of insulin secretion by somatostatin is disrupted in Cplx 2 KO islets. On the contrary, deletion of Cplx 2 did not affect the paracrine inhibition of glucagon by somatostatin at elevated glucose levels. In both β- and α-cells, the secretion profiles are parallel to Ca²⁺ activity changes following somatostatin treatment of wild-type (WT) and Cplx 2 KO islets. The loss of paracrine inhibition of insulin secretion is substantiated by direct measurements of insulin vesicle fusion events in Cplx 2 KO islets. Together, these data show a differential role for Cplx 2 in regulating hormone secretion from pancreatic islets.<b>NEW & NOTEWORTHY</b> Complexin 2 (Cplx 2) is a small synaptic protein that functions to clamp and release the SNARE protein complex during exocytosis. We show that Cplx 2 has a direct inhibitory role in glucagon and somatostatin secretion from intact mouse islets. Furthermore, the deletion of Cplx 2 leads to disrupted inhibition of β-cell Ca²⁺ activity and insulin secretion by somatostatin. These findings highlight a differential regulatory role of Cplx 2 in hormone secretion from pancreatic islets.