M. Srivastava et al., Defects in inositol 1,4,5-trisphosphate receptor expression, Ca2+ signaling, and insulin secretion in the anx7(+/-) knockout mouse, P NAS US, 96(24), 1999, pp. 13783-13788
Citations number
30
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
The mammalian anx7 gene codes for a Ca2+-activated GTPase, which supports C
a2+/CTP-dependent secretion events and Ca2+ channel activities in vitro and
in vivo, To test whether anx7 might be involved in Ca2+ signaling in secre
ting pancreatic beta cells, we knocked out the anx7 gene in the mouse and t
ested the insulin-secretory properties of the beta cells. The nullizygous a
nx7 (-/-) phenotype is lethal at embryonic day 10 because of cerebral hemor
rhage. However, the heterozygous anx7 (+/-) mouse, although expressing only
low levels of ANX7 protein, is Viable and fertile. The anx7 (+/-) phenotyp
e is associated with a substantial defect in insulin secretion, although th
e insulin content of the islets, is 8- to 10-fold higher in the mutants tha
n in the normal littermate control. We infer from etectrophysiological stud
ies that both glucose-stimulated secretion and voltage-dependent Ca2+ chann
el functions are normal. However, electrooptical recordings indicate that t
he (+/-) mutation has caused a change in the ability of inositol 1,4,5-tris
phosphate (IP3)-generating agonists to release intracellular calcium. The p
rinciple molecular consequence of lower anx7 expression is a profound reduc
tion in IP3 receptor expression and function in pancreatic islets. The prof
ound increase in islets, beta cell number, and size may be a means of compe
nsating for less efficient insulin secretion by individual defective pancre
atic beta cells. This is a direct demonstration of a connection between glu
cose-activated insulin secretion and Ca2+ signaling through IP3-sensitive C
a2+ stores.