title: Defects in inositol 1,4,5-trisphosphate receptor expression, Ca(2+) signaling, and insulin secretion in the anx7(+/-) knockout mouse.
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.
authors.affiliation: Department of Anatomy, Institute for Molecular Medicine, Uniformed Services University School of Medicine, Bethesda, MD 20814, USA. msrivastava@usuhs.mil
authors.forename: M
authors.initials: M
authors.lastname: Srivastava
authors.forename: I
authors.initials: I
authors.lastname: Atwater
authors.forename: M
authors.initials: M
authors.lastname: Glasman
authors.forename: X
authors.initials: X
authors.lastname: Leighton
authors.forename: G
authors.initials: G
authors.lastname: Goping
authors.forename: H
authors.initials: H
authors.lastname: Caohuy
authors.forename: G
authors.initials: G
authors.lastname: Miller
authors.forename: J
authors.initials: J
authors.lastname: Pichel
authors.forename: H
authors.initials: H
authors.lastname: Westphal
authors.forename: D
authors.initials: D
authors.lastname: Mears
authors.forename: E
authors.initials: E
authors.lastname: Rojas
authors.forename: H B
authors.initials: HB
authors.lastname: Pollard
mesh_terms: D000818:Animals; D017310:Annexin A7 / Q000235:genetics / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000096:biosynthesis*; D020013:Calcium Signaling; D002460:Cell Line; D003600:Cytosol; D004594:Electrophysiology; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000502:physiology*; D005822:Genetic Vectors; D005947:Glucose / Q000378:metabolism; D006965:Hyperplasia; D006984:Hypertrophy; D007150:Immunohistochemistry; D015544:Inositol 1,4,5-Trisphosphate; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016296:Mutagenesis; D010641:Phenotype; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis*
chemical_list: D017310:Annexin A7; D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007328:Insulin; D018160:Receptors, Cytoplasmic and Nuclear; D015544:Inositol 1,4,5-Trisphosphate; D020558:GTP Phosphohydrolases; D005947:Glucose; D002118:Calcium