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Differential roles of NHERF1, NHERF2, and PDZK1 in regulating CFTR-mediated intestinal anion secretion in mice
- Source :
- Journal of Clinical Investigation, 119(3), 540-550. The American Society for Clinical Investigation
- Publication Year :
- 2009
-
Abstract
- The epithelial anion channel CFTR interacts with multiple PDZ domain-containing proteins. Heterologous expression studies have demonstrated that the Na+/1H(+) exchanger regulatory factors, NHERF1, NHERF2, and PDZK1 (NHERF3), modulate CFTR membrane retention, conductivity, and interactions with other transporters. To study their biological roles in vivo, we investigated CFTR-dependent duodenal HCO3- secretion in mouse models of Nberf1, Nberf2, and Pdzk1 loss of function. We found that Nberf1 ablation strongly reduced basal as well as forskolin-stimulated (FSK-stimulated) HCO3- secretory rates and blocked beta(2)-adrenergic receptor (beta(2)-AR) stimulation. Conversely, Nberf2(-/-) mice displayed augmented FSK-stimulated HCO3- secretion. Furthermore, although lysophosphatidic acid (LPA) inhibited FSK-stimulated HCO3- secretion in WT mice, this effect was lost in Nberf2(-/-) mice. Pdzk1 ablation reduced basal, but not FSK-stimulated, HCO3- secretion. In addition, laser microdissection and quantitative PCR revealed that the beta(2)-AR and the type 2 LPA receptor were expressed together with CFTR in duodenal crypts and that colocalization of the beta(2)-AR and CFTR was reduced in the Nberf1(-/-) mice. These data suggest that the NHERF proteins differentially modulate duodenal HCO3- secretion: while NHERF1 is an obligatory linker for beta(2)-AR stimulation of CFTR, NHERF2 confers inhibitory signals by coupling the LPA receptor to CFTR.
- Subjects :
- Anions
Sodium-Hydrogen Exchangers
Duodenum
PDZ domain
Cystic Fibrosis Transmembrane Conductance Regulator
Stimulation
Mice
chemistry.chemical_compound
Lysophosphatidic acid
Animals
Secretion
Receptor
Mice, Knockout
Intestinal Secretions
biology
Cell Membrane
Colforsin
Intracellular Signaling Peptides and Proteins
Membrane Proteins
Colocalization
Epithelial Cells
General Medicine
respiratory system
Phosphoproteins
Molecular biology
Cystic fibrosis transmembrane conductance regulator
Bicarbonates
Sodium–hydrogen antiporter
chemistry
biology.protein
Receptors, Adrenergic, beta-2
Lysophospholipids
Gene Deletion
Research Article
Subjects
Details
- ISSN :
- 00219738
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation, 119(3), 540-550. The American Society for Clinical Investigation
- Accession number :
- edsair.doi.dedup.....b0c324770f0710da686fcc5361dd8a8b