Defects in inositol 1,4,5-trisphosphate receptor expression, Ca²⁺ signaling, and insulin secretion in the anx7(+/-) knockout mouse

The mammalian anx7 gene codes for a Ca²⁺-activated GTPase, which supports Ca²⁺/GTP-dependent secretion events and Ca²⁺ channel activities in vitro and in vivo. To test whether anx7 might be involved in Ca²⁺ signaling in secreting pancreatic β cells, we knocked out the anx7 gene in the mouse and tested the insulin-secretory properties of the β cells. The nullizygous anx7 (-/-) phenotype is lethal at embryonic day 10 because of cerebral hemorrhage. However, the heterozygous anx7 (+/-) mouse, although expressing only low levels of ANX7 protein, is viable and fertile. The anx7 (+/-) phenotype is associated with a substantial defect in insulin secretion, although the insulin content of the islets, is 8- to 10-fold higher in the mutants than in the normal littermate control. We infer from electrophysiological studies that both glucose-stimulated secretion and voltage-dependent Ca²⁺ channel functions are normal. However, electrooptical recordings indicate that the (+/-) mutation has caused a change in the ability of inositol 1,4,5-trisphosphate (IP₃)-generating agonists to release intracellular calcium. The principle molecular consequence of lower anx7 expression is a profound reduction in IP₃ receptor expression and function in pancreatic islets. The profound increase in islets, β cell number, and size may be a means of compensating for less efficient insulin secretion by individual defective pancreatic β cells. This is a direct demonstration of a connection between glucose-activated insulin secretion and Ca²⁺ signaling through IP₃-sensitive Ca²⁺ stores.