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Defects in inositol 1,4,5-trisphosphate receptor expression, Ca(2+) signaling, and insulin secretion in the anx7(+/-) knockout mouse.

The mammalian anx7 gene codes for a Ca(2+)-activated GTPase, which supports Ca(2+)/GTP-dependent secretion events and Ca(2+) channel activities in vitro and in vivo. To test whether anx7 might be involved in Ca(2+) signaling in secreting pancreatic beta cells, we knocked out the anx7 gene in the mouse and tested the insulin-secretory properties of the beta 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 Ca(2+) channel functions are normal. However, electrooptical recordings indicate that the (+/-) mutation has caused a change in the ability of inositol 1,4,5-trisphosphate (IP(3))-generating agonists to release intracellular calcium. The principle molecular consequence of lower anx7 expression is a profound reduction in IP(3) receptor expression and function in pancreatic islets. The profound increase in islets, beta cell number, and size may be a means of compensating for less efficient insulin secretion by individual defective pancreatic beta cells. This is a direct demonstration of a connection between glucose-activated insulin secretion and Ca(2+) signaling through IP(3)-sensitive Ca(2+) stores.

Pubmed ID: 10570150

Authors

  • Srivastava M
  • Atwater I
  • Glasman M
  • Leighton X
  • Goping G
  • Caohuy H
  • Miller G
  • Pichel J
  • Westphal H
  • Mears D
  • Rojas E
  • Pollard HB

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

November 23, 1999

Associated Grants

None

Mesh Terms

  • Animals
  • Annexin A7
  • Calcium
  • Calcium Channels
  • Calcium Signaling
  • Cell Line
  • Cytosol
  • Electrophysiology
  • GTP Phosphohydrolases
  • Genetic Vectors
  • Glucose
  • Hyperplasia
  • Hypertrophy
  • Immunohistochemistry
  • Inositol 1,4,5-Trisphosphate
  • Inositol 1,4,5-Trisphosphate Receptors
  • Insulin
  • Islets of Langerhans
  • Mice
  • Mice, Knockout
  • Mutagenesis
  • Phenotype
  • Receptors, Cytoplasmic and Nuclear