Inositol hexakisphosphate stimulates non-Ca(2+)-mediated and primes Ca(2+)-mediated exocytosis of insulin by activation of protein kinase C

d-myo-inositol 1,2,3,4,5,6-hexakisphosphate (InsP(6)), formed via complex pathways of inositol phosphate metabolism, composes the main bulk of inositol polyphosphates in the cell. Relatively little is known regarding possible biological functions for InsP(6). We now show that InsP(6) can modulate insulin exocytosis in permeabilized insulin-secreting cells. Concentrations of InsP(6) above 20 μM stimulated insulin secretion at basal Ca(2+)-concentration (30 nM) and primed Ca(2+)-induced exocytosis (10 μM), both effects being due to activation of protein kinase C. Our results suggest that InsP(6) can play an important modulatory role in the regulation of processes such as exocytosis in insulin-secreting cells. The specific role for InsP(6) can then be to recruit secretory granules to the site of exocytosis.