PMID- 10318832
OWN - NLM
STAT- MEDLINE
DCOM- 19990617
LR  - 20190508
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 20
DP  - 1999 May 14
TI  - cAMP-dependent mobilization of intracellular Ca2+ stores by activation of
      ryanodine receptors in pancreatic beta-cells. A Ca2+ signaling system stimulated 
      by the insulinotropic hormone glucagon-like peptide-1-(7-37).
PG  - 14147-56
AB  - Glucagon-like peptide-1 (GLP-1) is an intestinally derived insulinotropic hormone
      currently under investigation for use as a novel therapeutic agent in the
      treatment of type 2 diabetes mellitus. In vitro studies of pancreatic islets of
      Langerhans demonstrated that GLP-1 interacts with specific beta-cell G
      protein-coupled receptors, thereby facilitating insulin exocytosis by raising
      intracellular levels of cAMP and Ca2+. Here we report that the stimulatory
      influence of GLP-1 on Ca2+ signaling results, in part, from cAMP-dependent
      mobilization of ryanodine-sensitive Ca2+ stores. Studies of human, rat, and mouse
      beta-cells demonstrate that the binding of a fluorescent derivative of ryanodine 
      (BODIPY FL-X ryanodine) to its receptors is specific, reversible, and of high
      affinity. Rat islets and BTC3 insulinoma cells are shown by reverse transcriptase
      polymerase chain reaction analyses to express mRNA corresponding to the type 2
      isoform of ryanodine receptor-intracellular Ca2+ release channel (RYR2).
      Single-cell measurements of [Ca2+]i using primary cultures of rat and human
      beta-cells indicate that GLP-1 facilitates Ca2+-induced Ca2+ release (CICR),
      whereby mobilization of Ca2+ stores is triggered by influx of Ca2+ through L-type
      Ca2+ channels. In these cells, GLP-1 is shown to interact with metabolism of
      D-glucose to produce a fast transient increase of [Ca2+]i. This effect is
      reproduced by 8-Br-cAMP, but is blocked by a GLP-1 receptor antagonist
      (exendin-(9-39)), a cAMP antagonist ((Rp)-cAMPS), an L-type Ca2+ channel
      antagonist (nimodipine), an antagonist of the sarco(endo)plasmic reticulum Ca2+
      ATPase (thapsigargin), or by ryanodine. Characterization of the CICR mechanism by
      voltage clamp analysis also demonstrates a stimulation of Ca2+ release by
      caffeine. These findings provide new support for a model of beta-cell signal
      transduction whereby GLP-1 promotes CICR by sensitizing intracellular Ca2+
      release channels to the stimulatory influence of cytosolic Ca2+.
FAU - Holz, G G
AU  - Holz GG
AD  - Diabetes Unit, Massachusetts General Hospital, Harvard Medical School, Boston,
      Massachusetts 02114, USA. holz@helix.mgh.harvard.edu
FAU - Leech, C A
AU  - Leech CA
FAU - Heller, R S
AU  - Heller RS
FAU - Castonguay, M
AU  - Castonguay M
FAU - Habener, J F
AU  - Habener JF
LA  - eng
GR  - DK-52166/DK/NIDDK NIH HHS/United States
GR  - DK-30834/DK/NIDDK NIH HHS/United States
GR  - R01 DK030834/DK/NIDDK NIH HHS/United States
GR  - DK-45817/DK/NIDDK NIH HHS/United States
GR  - R01 DK045817/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)
RN  - 0 (Boron Compounds)
RN  - 0 (Fluorescent Dyes)
RN  - 0 (Peptide Fragments)
RN  - 0 (Protein Precursors)
RN  - 0 (RNA, Messenger)
RN  - 0 (Ryanodine Receptor Calcium Release Channel)
RN  - 15662-33-6 (Ryanodine)
RN  - 3G6A5W338E (Caffeine)
RN  - 89750-14-1 (Glucagon-Like Peptide 1)
RN  - 9007-92-5 (Glucagon)
RN  - E0399OZS9N (Cyclic AMP)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Boron Compounds
MH  - Caffeine/pharmacology
MH  - Calcium/*metabolism
MH  - Cyclic AMP/*metabolism
MH  - Fluorescent Dyes
MH  - Glucagon/*physiology
MH  - Glucagon-Like Peptide 1
MH  - Humans
MH  - Islets of Langerhans/drug effects/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Peptide Fragments/*physiology
MH  - Polymerase Chain Reaction
MH  - Protein Precursors/*physiology
MH  - RNA, Messenger/metabolism
MH  - Rats
MH  - Ryanodine/metabolism
MH  - Ryanodine Receptor Calcium Release Channel/*metabolism
MH  - *Signal Transduction
MH  - Tumor Cells, Cultured
PMC - PMC3508791
MID - NIHMS420681
EDAT- 1999/05/13 00:00
MHDA- 1999/05/13 00:01
CRDT- 1999/05/13 00:00
PHST- 1999/05/13 00:00 [pubmed]
PHST- 1999/05/13 00:01 [medline]
PHST- 1999/05/13 00:00 [entrez]
AID - 10.1074/jbc.274.20.14147 [doi]
PST - ppublish
SO  - J Biol Chem. 1999 May 14;274(20):14147-56. doi: 10.1074/jbc.274.20.14147.