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 C a2+/CTP-dependent secretion events and Ca2+ channel activities in vitro and in vivo, To test whether anx7 might be involved in Ca2+ signaling in secre ting pancreatic beta cells, we knocked out the anx7 gene in the mouse and t ested the insulin-secretory properties of the beta cells. The nullizygous a nx7 (-/-) phenotype is lethal at embryonic day 10 because of cerebral hemor rhage. However, the heterozygous anx7 (+/-) mouse, although expressing only low levels of ANX7 protein, is Viable and fertile. The anx7 (+/-) phenotyp e is associated with a substantial defect in insulin secretion, although th e insulin content of the islets, is 8- to 10-fold higher in the mutants tha n in the normal littermate control. We infer from etectrophysiological stud ies that both glucose-stimulated secretion and voltage-dependent Ca2+ chann el functions are normal. However, electrooptical recordings indicate that t he (+/-) mutation has caused a change in the ability of inositol 1,4,5-tris phosphate (IP3)-generating agonists to release intracellular calcium. The p rinciple molecular consequence of lower anx7 expression is a profound reduc tion in IP3 receptor expression and function in pancreatic islets. The prof ound increase in islets, beta cell number, and size may be a means of compe nsating for less efficient insulin secretion by individual defective pancre atic beta cells. This is a direct demonstration of a connection between glu cose-activated insulin secretion and Ca2+ signaling through IP3-sensitive C a2+ stores.