PMID- 10570150
OWN - NLM
STAT- MEDLINE
DCOM- 20000106
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 96
IP  - 24
DP  - 1999 Nov 23
TI  - Defects in inositol 1,4,5-trisphosphate receptor expression, Ca(2+) signaling,
      and insulin secretion in the anx7(+/-) knockout mouse.
PG  - 13783-8
AB  - 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.
FAU - Srivastava, M
AU  - Srivastava M
AD  - Department of Anatomy, Institute for Molecular Medicine, Uniformed Services
      University School of Medicine, Bethesda, MD 20814, USA. msrivastava@usuhs.mil
FAU - Atwater, I
AU  - Atwater I
FAU - Glasman, M
AU  - Glasman M
FAU - Leighton, X
AU  - Leighton X
FAU - Goping, G
AU  - Goping G
FAU - Caohuy, H
AU  - Caohuy H
FAU - Miller, G
AU  - Miller G
FAU - Pichel, J
AU  - Pichel J
FAU - Westphal, H
AU  - Westphal H
FAU - Mears, D
AU  - Mears D
FAU - Rojas, E
AU  - Rojas E
FAU - Pollard, H B
AU  - Pollard HB
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Annexin A7)
RN  - 0 (Calcium Channels)
RN  - 0 (Inositol 1,4,5-Trisphosphate Receptors)
RN  - 0 (Insulin)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 85166-31-0 (Inositol 1,4,5-Trisphosphate)
RN  - EC 3.6.1.- (GTP Phosphohydrolases)
RN  - IY9XDZ35W2 (Glucose)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Annexin A7/genetics/*physiology
MH  - Calcium/metabolism
MH  - Calcium Channels/*biosynthesis
MH  - *Calcium Signaling
MH  - Cell Line
MH  - Cytosol
MH  - Electrophysiology
MH  - GTP Phosphohydrolases/genetics/*physiology
MH  - Genetic Vectors
MH  - Glucose/metabolism
MH  - Hyperplasia
MH  - Hypertrophy
MH  - Immunohistochemistry
MH  - *Inositol 1,4,5-Trisphosphate
MH  - Inositol 1,4,5-Trisphosphate Receptors
MH  - Insulin/*metabolism
MH  - Insulin Secretion
MH  - Islets of Langerhans/cytology/metabolism/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Mutagenesis
MH  - Phenotype
MH  - Receptors, Cytoplasmic and Nuclear/*biosynthesis
PMC - PMC24142
EDAT- 1999/11/26 00:00
MHDA- 1999/11/26 00:01
CRDT- 1999/11/26 00:00
PHST- 1999/11/26 00:00 [pubmed]
PHST- 1999/11/26 00:01 [medline]
PHST- 1999/11/26 00:00 [entrez]
AID - 10.1073/pnas.96.24.13783 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):13783-8. doi:
      10.1073/pnas.96.24.13783.