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Irbit Mediates Synergy Between Ca2+ and cAMP Signaling Pathways During Epithelial Transport in Mice
- Source :
- Gastroenterology. 145:232-241
- Publication Year :
- 2013
- Publisher :
- Elsevier BV, 2013.
-
Abstract
- Background & Aims The cyclic adenosine monophosphate (cAMP) and Ca 2+ signaling pathways synergize to regulate many physiological functions. However, little is known about the mechanisms by which these pathways interact. We investigated the synergy between these signaling pathways in mouse pancreatic and salivary gland ducts. Methods We created mice with disruptions in genes encoding the solute carrier family 26, member 6 (Slc26a6 −/− mice) and inositol 1,4,5-triphosphate (InsP 3 ) receptor-binding protein released with InsP 3 (Irbit −/− ) mice. We investigated fluid secretion by sealed pancreatic ducts and the function of Slc26a6 and the cystic fibrosis transmembrane conductance regulator (CFTR) in HeLa cells and in ducts isolated from mouse pancreatic and salivary glands. Slc26a6 activity was assayed by measuring intracellular pH, and CFTR activity was assayed by measuring Cl – current. Protein interactions were determined by immunoprecipitation analyses. Results Irbit mediated the synergistic activation of CFTR and Slc26a6 by Ca 2+ and cAMP. In resting cells, Irbit was sequestered by InsP 3 receptors (IP 3 Rs) in the endoplasmic reticulum. Stimulation of Gs-coupled receptors led to phosphorylation of IP 3 Rs, which increased their affinity for InsP 3 and reduced their affinity for Irbit. Subsequent weak stimulation of Gq-coupled receptors, which led to production of low levels of IP 3 , caused dissociation of Irbit from IP 3 Rs and allowed translocation of Irbit to CFTR and Slc26a6 in the plasma membrane. These processes stimulated epithelial secretion of electrolytes and fluid. These pathways were not observed in pancreatic and salivary glands from Irbit −/− or Slc26a6 −/− mice, or in salivary gland ducts expressing mutant forms of IP 3 Rs that could not undergo protein kinase A–mediated phosphorylation. Conclusions Irbit promotes synergy between the Ca 2+ and cAMP signaling pathways in cultured cells and in pancreatic and salivary ducts from mice. Defects in this pathway could be involved in cystic fibrosis, pancreatitis, or Sjogren syndrome.
- Subjects :
- Cystic Fibrosis Transmembrane Conductance Regulator
Inositol 1,4,5-Trisphosphate
Antiporters
Epithelium
Article
Mice
chemistry.chemical_compound
Cyclic AMP
medicine
Animals
Inositol 1,4,5-Trisphosphate Receptors
Salivary Ducts
Secretion
Cyclic adenosine monophosphate
Phosphorylation
Protein kinase A
G protein-coupled receptor
Hepatology
biology
Salivary gland
Adenosylhomocysteinase
Pancreatic Ducts
Gastroenterology
Biological Transport
Cyclic AMP-Dependent Protein Kinases
Molecular biology
Cystic fibrosis transmembrane conductance regulator
medicine.anatomical_structure
chemistry
Sulfate Transporters
biology.protein
Calcium
Signal transduction
Signal Transduction
Subjects
Details
- ISSN :
- 00165085
- Volume :
- 145
- Database :
- OpenAIRE
- Journal :
- Gastroenterology
- Accession number :
- edsair.doi.dedup.....95595a269b7d1c3aa4acf1746e106a42