SNAP-25b-deficiency increases insulin secretion and changes spatiotemporal profile of Ca(2+)oscillations in β cell networks

SNAP-25 is a protein of the core SNARE complex mediating stimulus-dependent release of insulin from pancreatic β cells. The protein exists as two alternatively spliced isoforms, SNAP-25a and SNAP-25b, differing in 9 out of 206 amino acids, yet their specific roles in pancreatic β 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 Ca(2+) in β cells within pancreatic slices showed no significant differences in Ca(2+)-sensitivity, amplitude or rate of exocytosis between SNAP-25b-deficient and wild-type littermates. Therefore, we next investigated if Ca(2+) handling was affected in glucose-stimulated β cells using intracellular Ca(2+)-imaging and found premature activation and delayed termination of [Ca(2+)](i) elevations. These findings were accompanied by less synchronized Ca(2+)-oscillations and hence more segregated functional β 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 β cells, except for participating in the core SNARE complex, is necessary for accurate regulation of Ca(2+)-dynamics.