Inositol hexakisphosphate and β-cell stimulus-secretion coupling

Inositol hexakisphosphate (InsP(6)) inhibits serine/threonine protein phosphatases type-1 (pp1), type-2A (PP2A) and type-3 (PP3) in a concentration-dependent manner. Since the activity of voltage-gated L-type Ca2+-channels is increased by inhibition of serine/threonine protein phosphatases, this may explain the increased Ca2+-channel activity obtained in the presence of InsP(6). In insulin- secreting cells, InsP(6) is therefore likely to be one of the key elements modulating Ca2+-influx over the plasma membrane. InsP(6) can also modulate insulin exocytosis in permeabilized cells. Concentrations of InsP(6) above 20 mu M stimulated insulin secretion at basal Ca2+-concentration (30 nM) and primed Ca2+-induced exocytosis (10 mu M), both effects being due to activation of PKC. Hence, InsP(6) can play an important modulatory role in the regulation of insulin exocytosis and the specific role may then be to recruit secretory granules to the site of exocytosis. The fact that some InsP(6) is localised to membranes, so being topographically disposed to regulate ion channels as well as exocytosis, and that it has a rapid rate of turnover in glucose-stimulated insulin-secreting cells, suggest novel functions for InsP(6) in the insulin secretory process.