Inositol hexakisphosphate and beta-cell stimulus-secretion coupling.
Inositol hexakisphosphate (InsP6) 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 Ca(2+)-channels is increased by inhibition of serine/threonine protein phosphatases, this may explain trhe increased Ca(2+)-channel activity obtained in the presence of InsP6. In insulin-secreting cells, InsP6 is therefore likely to be one of the key elements modulating Ca(2+)-influx over the plasma membrane. InsP6 can also modulate insulin exocytosis in permeabilized cells. Concentrations of InsP6 above 20 microM stimulated insulin secretion at basal Ca(2+)-concentration (30 nM) and primed Ca(2+)-induced exocytosis (10 microM), both effects being due to activation of PKC. Hence, InsP6 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 InsP6 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 InsP6 in the insulin secretory process.
Barker
C J
CJ
Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden.
Berggren
P O
PO
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects; D005089:Exocytosis / Q000187:drug effects; D006801:Humans; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010833:Phytic Acid / Q000494:pharmacology*
D015220:Calcium Channels; D010833:Phytic Acid; D010749:Phosphoprotein Phosphatases