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IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway
- Source :
- The Journal of clinical investigation. 121(3)
- Publication Year :
- 2010
-
Abstract
- Fluid and HCO(3)(-) secretion are fundamental functions of epithelia and determine bodily fluid volume and ionic composition, among other things. Secretion of ductal fluid and HCO(3)(-) in secretory glands is fueled by Na(+)/HCO(3)(-) cotransport mediated by basolateral solute carrier family 4 member 4 (NBCe1-B) and by Cl(-)/HCO(3)(-) exchange mediated by luminal solute carrier family 26, member 6 (Slc26a6) and CFTR. However, the mechanisms governing ductal secretion are not known. Here, we have shown that pancreatic ductal secretion in mice is suppressed by silencing of the NBCe1-B/CFTR activator inositol-1,4,5-trisphosphate (IP(3)) receptor-binding protein released with IP(3) (IRBIT) and by inhibition of protein phosphatase 1 (PP1). In contrast, silencing the with-no-lysine (WNK) kinases and Ste20-related proline/alanine-rich kinase (SPAK) increased secretion. Molecular analysis revealed that the WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, in addition to stimulating their activities. Silencing of SPAK and IRBIT in the same ducts rescued ductal secretion due to silencing of IRBIT alone. These findings stress the pivotal role of IRBIT in epithelial fluid and HCO(3)(-) secretion and provide a molecular mechanism by which IRBIT coordinates these processes. They also have implications for WNK/SPAK kinase-regulated processes involved in systemic fluid homeostasis, hypertension, and cystic fibrosis.
- Subjects :
- medicine.medical_specialty
Cystic Fibrosis Transmembrane Conductance Regulator
Protein Serine-Threonine Kinases
Minor Histocompatibility Antigens
Mice
WNK Lysine-Deficient Protein Kinase 1
Internal medicine
Protein Phosphatase 1
medicine
SLC26A6
Gene silencing
Animals
Humans
Parotid Gland
Secretion
Lectins, C-Type
Gene Silencing
biology
Kinase
urogenital system
Adenosylhomocysteinase
Sodium-Bicarbonate Symporters
Intracellular Signaling Peptides and Proteins
Pancreatic Ducts
Membrane Proteins
Protein phosphatase 1
General Medicine
Cystic fibrosis transmembrane conductance regulator
Solute carrier family
Endocrinology
Gene Expression Regulation
biology.protein
Phosphorylation
Female
Research Article
Subjects
Details
- ISSN :
- 15588238
- Volume :
- 121
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- The Journal of clinical investigation
- Accession number :
- edsair.doi.dedup.....9508ef82f6a92fbc580694f20047e467