The Anx7(+/-) knockout mutation alters electrical and secretory responses to Ca ²⁺ -mobilizing agents in pancreatic β-cells

Insulin secretion from the pancreatic β-cell is controlled by changes in membrane potential and intracellular Ca ²⁺ . The contribution of intracellular Ca ²⁺ 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 IP ₃ receptors and defects in IP ₃ -dependent Ca ²⁺ signaling. To further elucidate the effect of the Anx7(+/-) mutation on signaling related to intracellular Ca ²⁺ stores in the β-cell, we measured the effects of Ca ²⁺ mobilizing agents on electrical activity, intracellular Ca ²⁺ 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 ²⁺ mobilization was not affected by the Anx7(+/-) mutation, suggesting that the mechanism underlying the observed differences in electrical and secretory responsiveness does not involve intracellular Ca ²⁺ stores. Our results provide evidence that both IP ₃ receptors and ryanodine receptors play important roles in regulating β-cell membrane potential and insulin secretion, and that the Anx7(+/-) mutation is associated with alterations in the signaling pathways related to these receptors.