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Defects in inositol 1,4,5-trisphosphate receptor expression, Ca(2+) signaling, and insulin secretion in the anx7(+/-)
M Srivastava1, I Atwater, M Glasman
1Department of Anatomy, Institute for Molecular Medicine, Uniformed Services University School of Medicine, Bethesda, MD 20814, USA. msrivastava@usuhs.mil
Abstract:
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.
Insights
The anx7 gene is crucial for insulin secretion in pancreatic beta cells. Reduced anx7 levels impair calcium signaling, leading to defective insulin release, despite increased beta cell mass.
Area of Science:
- Cell Biology
- Endocrinology
- Molecular Biology
Background:
- The anx7 gene encodes a Ca(2+)-activated GTPase involved in secretion and Ca(2+) channel activity.
- Anx7's role in pancreatic beta cell Ca(2+) signaling and insulin secretion was previously unclear.
Purpose of the Study:
- To investigate the function of the anx7 gene in pancreatic beta cell insulin secretion.
- To elucidate the molecular mechanisms underlying anx7's involvement in Ca(2+) signaling.
Main Methods:
- Gene knockout in mice (anx7 (-/-) and anx7 (+/-)).
- Assessment of insulin secretion and content in pancreatic islets.
- Electrophysiological studies and electrooptical recordings.
- Analysis of inositol 1,4,5-trisphosphate (IP(3)) receptor expression and function.
Main Results:
- Heterozygous anx7 (+/-) mice exhibit defective insulin secretion but increased insulin content and beta cell mass.
- Glucose-stimulated secretion and voltage-dependent Ca(2+) channels function normally.
- Anx7 deficiency impairs Ca(2+) release mediated by IP(3)-generating agonists.
- Reduced anx7 expression leads to decreased IP(3) receptor expression and function.
Conclusions:
- Anx7 is essential for proper Ca(2+) signaling and insulin secretion in pancreatic beta cells.
- Defective Ca(2+) release via IP(3) receptors is a key consequence of reduced anx7 levels.
- Increased beta cell mass may compensate for impaired insulin secretion in anx7 (+/-) mice.