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T he 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 β₂-adrenergic receptor (β₂-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 β₂-AR and the type 2 LPA receptor were expressed together with CFTR in duodenal crypts and that colocalization of the β₂-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 β₂-AR stimulation of CFTR, NHERF2 confers inhibitory signals by coupling the LPA receptor to CFTR.