Differential roles of NHERF1, NHERF2, and PDZK1 in regulating CFTR-mediated intestinal anion secretion in mice

J Clin Invest. 2009 Mar;119(3):540-50. doi: 10.1172/JCI35541. Epub 2009 Feb 16.


The epithelial anion channel CFTR interacts with multiple PDZ domain-containing proteins. Heterologous expression studies have demonstrated that the Na+/H+ 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 Nherf1, Nherf2, and Pdzk1 loss of function. We found that Nherf1 ablation strongly reduced basal as well as forskolin-stimulated (FSK-stimulated) HCO3- secretory rates and blocked beta2-adrenergic receptor (beta2-AR) stimulation. Conversely, Nherf2-/- 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 Nherf2-/- mice. Pdzk1 ablation reduced basal, but not FSK-stimulated, HCO3- secretion. In addition, laser microdissection and quantitative PCR revealed that the beta2-AR and the type 2 LPA receptor were expressed together with CFTR in duodenal crypts and that colocalization of the beta2-AR and CFTR was reduced in the Nherf1-/- mice. These data suggest that the NHERF proteins differentially modulate duodenal HCO3- secretion: while NHERF1 is an obligatory linker for beta2-AR stimulation of CFTR, NHERF2 confers inhibitory signals by coupling the LPA receptor to CFTR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anions / metabolism
  • Bicarbonates / metabolism
  • Cell Membrane / physiology
  • Colforsin / antagonists & inhibitors
  • Colforsin / pharmacology
  • Cystic Fibrosis Transmembrane Conductance Regulator / physiology*
  • Duodenum / metabolism
  • Epithelial Cells / drug effects
  • Epithelial Cells / physiology
  • Gene Deletion
  • Intestinal Secretions / physiology*
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Lysophospholipids / pharmacology
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Phosphoproteins / deficiency
  • Phosphoproteins / genetics
  • Phosphoproteins / physiology*
  • Receptors, Adrenergic, beta-2 / drug effects
  • Receptors, Adrenergic, beta-2 / physiology
  • Sodium-Hydrogen Exchangers / genetics
  • Sodium-Hydrogen Exchangers / physiology*


  • Anions
  • Bicarbonates
  • Intracellular Signaling Peptides and Proteins
  • Lysophospholipids
  • Membrane Proteins
  • PDZK1 protein, mouse
  • Phosphoproteins
  • Receptors, Adrenergic, beta-2
  • Sodium-Hydrogen Exchangers
  • sodium-hydrogen exchanger regulatory factor
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Colforsin
  • lysophosphatidic acid