Removal of Ca super(2+) Channel beta sub(3) Subunit Enhances Ca super(2+) Oscillation Frequency and Insulin Exocytosis

An oscillatory increase in pancreatic beta cell cytoplasmic free Ca super(2+) concentration, [Ca super(2+)] sub(i), is a key feature in glucose-induced insulin release. The role of the voltage-gated Ca super(2+) channel beta sub(3) subunit in the molecular regulation of these [Ca super(2+)] sub(i) oscillations has now been clarified by using beta sub(3) subunit-deficient beta cells. beta sub(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 [Ca super(2+)] sub(i) oscillation frequency in beta cells lacking the beta sub(3) subunit, an effect accounted for by enhanced formation of inositol 1,4,5-trisphosphate (InsP sub(3)) and increased Ca super(2+) mobilization from intracellular stores. Hence, the beta sub(3) subunit negatively modulated InsP sub(3)-induced Ca super(2+) release, which is not paralleled by any effect on the voltage-gated L type Ca super(2+) channel. Since the increase in insulin release was manifested only at high glucose concentrations, blocking the beta sub(3) subunit in the beta cell may constitute the basis for a novel diabetes therapy.