title: The Anx7(+/-) knockout mutation alters electrical and secretory responses to Ca(2+)-mobilizing agents in pancreatic β-cells.
abstract: Insulin secretion from the pancreatic β-cell is controlled by changes in membrane potential and intracellular Ca(2+). The contribution of intracellular Ca(2+) stores to this process is poorly understood. We have previously shown that β-cells of mice lacking one copy of the Annexin 7 gene (Anx7(+/-)) express reduced levels of IP(3) receptors and defects in IP(3)-dependent Ca(2+) signaling. To further elucidate the effect of the Anx7(+/-) mutation on signaling related to intracellular Ca(2+) stores in the β-cell, we measured the effects of Ca(2+) mobilizing agents on electrical activity, intracellular Ca(2+) and insulin secretion in control and mutant β-cells. We found that the muscarinic agonist carbachol and the ryanodine receptor agonists caffeine and 4-chloro-m-cresol had more potent depolarizing effects on Anx7(+/-) β-cells compared to controls. Accordingly, glucose-induced insulin secretion was augmented to a greater extent by caffeine in mutant islets. Surprisingly, ryanodine receptor-mediated Ca(2+) mobilization was not affected by the Anx7(+/-) mutation, suggesting that the mechanism underlying the observed differences in electrical and secretory responsiveness does not involve intracellular Ca(2+) stores. Our results provide evidence that both IP3 receptors and ryanodine receptors play important roles in regulating β-cell membrane potential and insulin secretion, and that the Anx7(+/-) mutation is associated with alterations in the signaling pathways related to these receptors.
authors.affiliation: Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. dmears@usuhs.mil
authors.forename: David
authors.initials: D
authors.lastname: Mears
authors.forename: Charles L
authors.initials: CL
authors.lastname: Zimliki
authors.forename: Illani
authors.initials: I
authors.lastname: Atwater
authors.forename: Eduardo
authors.initials: E
authors.lastname: Rojas
authors.forename: Mirta
authors.initials: M
authors.lastname: Glassman
authors.forename: Ximena
authors.initials: X
authors.lastname: Leighton
authors.forename: Harvey B
authors.initials: HB
authors.lastname: Pollard
authors.forename: Meera
authors.initials: M
authors.lastname: Srivastava
mesh_terms: D000818:Animals; D017310:Annexin A7 / Q000235:genetics / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology*; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects
chemical_list: D017310:Annexin A7; C480504:Anxa7 protein, mouse; D007328:Insulin; D019837:Ryanodine Receptor Calcium Release Channel; D005947:Glucose; D002118:Calcium