Differential roles of NHERF1, NHERF2, and PDZK1 in regulating CFTR-mediated intestinal anion secretion in mice
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 Î²2-adrenergic receptor (Î²2-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 Î²2-AR and the type 2 LPA receptor were expressed together with CFTR in duodenal crypts and that colocalization of the Î²2-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 Î²2-AR stimulation of CFTR, NHERF2 confers inhibitory signals by coupling the LPA receptor to CFTR.
|Persistent URL||dx.doi.org/10.1172/JCI35541, hdl.handle.net/1765/33125|
Singh, A.K., Riederer, B., Krabbenhöft, A., Rausch, B., Bonhagen, J., Lehmann, U., … Seidler, U.. (2009). Differential roles of NHERF1, NHERF2, and PDZK1 in regulating CFTR-mediated intestinal anion secretion in mice. Journal of Clinical Investigation, 119(3), 540–550. doi:10.1172/JCI35541