The Anx7(+/-) knockout mutation alters electrical and secretory responses to Ca2+-mobilizing agents in pancreatic β-cells

Abstract

Insulin secretion from the pancreatic β-cell is controlled by changes in membrane potential and intracellular Ca2+. The contribution of intracellular Ca2+ stores to this process is poorly understood. We have previously shown that β-cells of mice lacking one copy of the Annexin 7 gene (Anx7(+/-)) express reduced levels of IP3 receptors and defects in IP3-dependent Ca2+ signaling. To further elucidate the effect of the Anx7(+/-) mutation on signaling related to intracellular Ca2+ stores in the β-cell, we measured the effects of Ca2+ mobilizing agents on electrical activity, intracellular Ca2+ and insulin secretion in control and mutant β-cells. We found that the muscarinic agonist carbachol and the ryanodine receptor agonists caffeine and 4-chloro-m-cresol had more potent depolarizing effects on Anx7(+/-) β-cells compared to controls. Accordingly, glucose-induced insulin secretion was augmented to a greater extent by caffeine in mutant islets. Surprisingly, ryanodine receptor-mediated Ca