Removal of Ca2+ channel β3 Subunit enhances Ca2+ oscillation frequency and insulin exocytosis

An oscillatory increase in pancreatic beta cell cytoplasmic free Ca2+ concentration, [Ca2+](i), is a key feature in glucose-induced insulin release. The role of the voltage-gated Ca2+ channel beta(3) subunit in the molecular regulation of these [Ca2+](i) oscillations has now been clarified by using beta(3) subunit-deficient beta cells. beta(3) knockout mice showed a more efficient glucose homeostasis compared to wild-type mice due to increased glucose-stimulated insulin secretion. This resulted from an increased glucose-induced [Ca2+](i) oscillation frequency in beta cells lacking the beta(3) subunit, an effect accounted for by enhanced formation of inositol 1,4,5-trisphosphate (InsP(3)) and increased Ca2+ mobilization from intracellular stores. Hence, the beta(3) subunit negatively modulated InsP(3)-induced Ca2+ release, which is not paralleled by any effect on the voltage-gated L type Ca2+ channel. Since the increase in insulin release was manifested only at high glucose concentrations, blocking the beta(3) subunit in the beta cell may constitute the basis for a novel diabetes therapy.