SNAP-25b-deficiency increases insulin secretion and changes spatiotemporal profile of Ca2+ oscillations in β cell networks

SNAP-25 is a protein of the core SNARE complex mediating stimulus-dependent release of insulin from pancreatic beta cells. The protein exists as two alternatively spliced isoforms, SNAP-25a and SNAP25b, differing in 9 out of 206 amino acids, yet their specific roles in pancreatic beta cells remain unclear. We explored the effect of SNAP-25b-deficiency on glucose-stimulated insulin release in islets and found increased secretion both in vivo and in vitro. However, slow photo-release of caged Ca2+ in beta cells within pancreatic slices showed no significant differences in Ca2+-sensitivity, amplitude or rate of exocytosis between SNAP-25b-deficient and wild-type littermates. Therefore, we next investigated if Ca2+ handling was affected in glucose-stimulated beta cells using intracellular Ca2+-imaging and found premature activation and delayed termination of [Ca2+] i elevations. These findings were accompanied by less synchronized Ca2+-oscillations and hence more segregated functional beta cell networks in SNAP-25b-deficient mice. Islet gross morphology and architecture were maintained in mutant mice, although sex specific compensatory changes were observed. Thus, our study proposes that SNAP-25b in pancreatic beta cells, except for participating in the core SNARE complex, is necessary for accurate regulation of Ca2+-dynamics.