Open AccessDefects in inositol 1,4,5-trisphosphate receptor expression, Ca 2+ signaling, and insulin secretion in the anx 7(+/−) knockout mouse
Author(s) -
Meera Srivastava,
I Atwater,
Mirta Glasman,
Ximena Leighton,
Gertrude Goping,
H. Caohuy,
Georgina Miller,
José G. Pichel,
Heiner Westphal,
David Mears,
Eduardo Rojas,
Harvey B. Pollard
Publication year - 1999
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.96.24.13783
Subject(s) - endocrinology , medicine , biology , insulin , pancreatic islets , inositol , inositol trisphosphate receptor , secretion , insulin receptor , signal transduction , insulin oscillation , inositol trisphosphate , beta cell , calcium in biology , insulin receptor substrate , islet , microbiology and biotechnology , receptor , intracellular , biochemistry , insulin resistance
The mammaliananx7 gene codes for a Ca2+ -activated GTPase, which supports Ca2+ /GTP-dependent secretion events and Ca2+ channel activitiesin vitro andin vivo . To test whetheranx7 might be involved in Ca2+ signaling in secreting pancreatic β cells, we knocked out theanx7 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.