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Generation of nicotinic acid adenine dinucleotide phosphate and cyclic ADP-ribose by glucagon-like peptide-1 evokes Ca2+ signal that is essential for insulin secretion in mouse pancreatic islets.
- Source :
-
Diabetes [Diabetes] 2008 Apr; Vol. 57 (4), pp. 868-78. Date of Electronic Publication: 2008 Jan 09. - Publication Year :
- 2008
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Abstract
- Objective: Glucagon-like peptide-1 (GLP-1) increases intracellular Ca(2+) concentrations ([Ca(2+)](i)), resulting in insulin secretion from pancreatic beta-cells. The molecular mechanism(s) of the GLP-1-mediated regulation of [Ca(2+)](i) was investigated.<br />Research Design and Methods: GLP-1-induced changes in [Ca(2+)](i) were measured in beta-cells isolated from Cd38(+/+) and Cd38(-/-) mice. Calcium-mobilizing second messengers were identified by measuring levels of nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic ADP-ribose (ADPR), using a cyclic enzymatic assay. To locate NAADP- and cyclic ADPR-producing enzyme(s), cellular organelles were separated using the sucrose gradient method.<br />Results: A GLP-1-induced [Ca(2+)](i) increase showed a cooperative Ca(2+) signal, i.e., an initial [Ca(2+)](i) rise mediated by the action of NAADP that was produced in acidic organelles and a subsequent long-lasting increase of [Ca(2+)](i) by the action of cyclic ADPR that was produced in plasma membranes and secretory granules. GLP-1 sequentially stimulated production of NAADP and cyclic ADPR in the organelles through protein kinase A and cAMP-regulated guanine nucleotide exchange factor II. Furthermore, the results showed that NAADP production from acidic organelles governed overall Ca(2+) signals, including insulin secretion by GLP-1, and that in addition to CD38, enzymes capable of synthesizing NAADP and/or cyclic ADPR were present in beta-cells. These observations were supported by the study with Cd38(-/-) beta-cells, demonstrating production of NAADP, cyclic ADPR, and Ca(2+) signal with normal insulin secretion stimulated by GLP-1.<br />Conclusions: Our findings demonstrate that the GLP-1-mediated Ca(2+) signal for insulin secretion in pancreatic beta-cells is a cooperative action of NAADP and cyclic ADPR spatiotemporally formed by multiple enzymes.
- Subjects :
- ADP-ribosyl Cyclase 1 deficiency
ADP-ribosyl Cyclase 1 genetics
Acetylcysteine analogs & derivatives
Acetylcysteine pharmacology
Animals
Endoplasmic Reticulum drug effects
Endoplasmic Reticulum physiology
Erythromycin analogs & derivatives
Erythromycin pharmacology
Insulin Secretion
Islets of Langerhans drug effects
Islets of Langerhans metabolism
Mice
Mice, Inbred ICR
Mice, Knockout
NADP biosynthesis
NADP pharmacology
Signal Transduction drug effects
Calcium physiology
Cyclic ADP-Ribose biosynthesis
Glucagon-Like Peptide 1 pharmacology
Insulin metabolism
Islets of Langerhans physiology
NADP analogs & derivatives
Signal Transduction physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1939-327X
- Volume :
- 57
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 18184929
- Full Text :
- https://doi.org/10.2337/db07-0443