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

Singh, Anurag Kumar; Riederer, Brigitte; Krabbenhöft, Anja; Rausch, Brigitte; Bonhagen, Janina; Lehmann, Ulrich; de Jonge, Hugo R.; Donowitz, Mark; Yun, Chris; Weinman, Edward J.; Kocher, Olivier; Hogema, Boris M.; Seidler, Ursula

doi:10.1172/jci35541

Cited by 364

The DOI matches its Crossref record; 52 of the 52 references it cites were found in a registry or an index.

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

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Singh, Anurag Kumar, Riederer, Brigitte, Krabbenhöft, Anja, Rausch, Brigitte, Bonhagen, Janina, Lehmann, Ulrich, de Jonge, Hugo R., Donowitz, Mark, Yun, Chris, Weinman, Edward J., Kocher, Olivier, Hogema, Boris M., Seidler, Ursula·2009·Journal of Clinical Investigation

DOI 10.1172/jci35541

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Abstract

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.

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See all 364

Authors: Singh, A. K., Riederer, B., Krabbenhöft, A., Rausch, B., Bonhagen, J., Lehmann, U., de Jonge, H. R., Donowitz, M., Yun, C., Weinman, E. J., Kocher, O., Hogema, B. M., & Seidler, U.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2009-03-02
Volume: 119
Issue: 3
Pages: 540-550
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci35541
OpenAlex: W2023857290
Cited by: 364
References: 52
FWCI: 26.93
Type: journal article
Language: en
Open access: bronze

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The paper: Singh, A. K., Riederer, B., Krabbenhöft, A., Rausch, B., Bonhagen, J., Lehmann, U., de Jonge, H. R., Donowitz, M., Yun, C., Weinman, E. J., Kocher, O., Hogema, B. M., & Seidler, U. (2009). Differential roles of NHERF1, NHERF2, and PDZK1 in regulating CFTR-mediated intestinal anion secretion in mice. Journal of Clinical Investigation. https://doi.org/10.1172/jci35541

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

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