Cav1.2 and Cav1.3 Are Differentially Coupled to Glucagon-Like Peptide-1 Potentiation of Glucose-Stimulated Insulin Secretion in the Pancreatic β-Cell Line INS-1
| Autor: | Sarah Melissa P. Jacobo, Gregory H. Hockerman, Marcy L. Guerra |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Phosphatidylinositol 4
5-Diphosphate Dihydropyridines endocrine system medicine.medical_specialty Thapsigargin Calcium Channels L-Type Gastric Inhibitory Polypeptide Cell Line Potassium Chloride Cav1.3 Wortmannin Calcium Channels T-Type chemistry.chemical_compound Glucagon-Like Peptide 1 Insulin-Secreting Cells Internal medicine medicine Animals Insulin Protein kinase A Protein Kinase C Protein kinase C Pharmacology biology Voltage-dependent calcium channel Ryanodine receptor Calcium Channel Blockers Cyclic AMP-Dependent Protein Kinases Stimulation Chemical Rats Endocrine and Diabetes Glucose Endocrinology chemistry Mutation biology.protein Molecular Medicine Indicators and Reagents Signal transduction hormones hormone substitutes and hormone antagonists Plasmids Signal Transduction |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 331:724-732 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.109.158519 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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