19710366

pubmed:Citation

2

The incretin peptides, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), potentiate glucose-stimulated insulin secretion (GSIS) and beta-cell proliferation and differentiation. Ca(2+) influx via voltage-gated L-type Ca(2+) channels is required for GLP-1 and GIP potentiation of GSIS. We investigated the role of the L-type Ca(2+) channels Ca(v)1.2 and Ca(v)1.3 in mediating GLP-1- and GIP-stimulated events in INS-1 cells and INS-1 cell lines expressing dihydropyridine-insensitive (DHPi) mutants of either Ca(v)1.2 or Ca(v)1.3. Ca(v)1.3/DHPi channels supported full potentiation of GSIS by GLP-1 (50 nM) compared with untransfected INS-1 cells. However, GLP-1-potentiated GSIS mediated by Ca(v)1.2/DHPi channels was markedly reduced compared with untransfected INS-1 cells. In contrast, GIP (10 nM) potentiation of GSIS mediated by both Ca(v)1.2/DHPi and Ca(v)1.3/DHPi channels was similar to that observed in untransfected INS-1 cells. Disruption of intracellular Ca(2+) release with thapsigargin, ryanodine, or 2-aminoethyldiphenylborate and inhibition of protein kinase A (PKA) or protein kinase C (PKC) significantly reduced GLP-1 potentiation of GSIS by Ca(v)1.3/DHPi channels and by endogenous L-type channels in INS-1 cells, but not by Ca(v)1.2/DHPi channels. Inhibition of glucose-stimulated phospholipase C activity with 1-(6-((17b-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122) did not inhibit potentiation of GSIS by GLP-1 in INS-1 cells. In contrast, wortmannin, an inhibitor of phosphatidylinositol 3-kinase, and 2'-amino-3'-methoxyflavone (PD98059), an inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase, both markedly inhibited GLP-1 potentiation of GSIS by endogenous channels in INS-1 cells and Ca(v)1.3/DHPi channels, but not by Ca(v)1.2/DHPi channels. Thus, Ca(v)1.3 is preferentially coupled to GLP-1 potentiation of GSIS in INS-1 cells via a mechanism that requires intact intracellular Ca(2+) stores, PKA and PKC activity, and activation of ERK1/2.

eng

IM

MEDLINE

1521-0103

Electronic

NLM

724-32

pubmed-meshheading:19710366-Animals, pubmed-meshheading:19710366-Calcium Channel Blockers, pubmed-meshheading:19710366-Calcium Channels, L-Type, pubmed-meshheading:19710366-Calcium Channels, T-Type, pubmed-meshheading:19710366-Cell Line, pubmed-meshheading:19710366-Cyclic AMP-Dependent Protein Kinases, pubmed-meshheading:19710366-Dihydropyridines, pubmed-meshheading:19710366-Gastric Inhibitory Polypeptide, pubmed-meshheading:19710366-Glucagon-Like Peptide 1, pubmed-meshheading:19710366-Glucose, pubmed-meshheading:19710366-Indicators and Reagents, pubmed-meshheading:19710366-Insulin, pubmed-meshheading:19710366-Insulin-Secreting Cells, pubmed-meshheading:19710366-Mutation, pubmed-meshheading:19710366-Phosphatidylinositol 4,5-Diphosphate, pubmed-meshheading:19710366-Plasmids, pubmed-meshheading:19710366-Potassium Chloride, pubmed-meshheading:19710366-Protein Kinase C, pubmed-meshheading:19710366-Rats, pubmed-meshheading:19710366-Signal Transduction, pubmed-meshheading:19710366-Stimulation, Chemical

Cav1.2 and Cav1.3 are differentially coupled to glucagon-like peptide-1 potentiation of glucose-stimulated insulin secretion in the pancreatic beta-cell line INS-1.

Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural