ArticleAmerican journal of physiology. Cell physiology2011
NHERF1 and NHERF2 are necessary for multiple but usually separate aspects of basal and acute regulation of NHE3 activity.
Article in American journal of physiology. Cell physiology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 55 citations in OpenAlex.
- Cystinosin regulates NaEMBO reports · 2026Article
- Klf2 as a potential regulator of the signaling Enos/Nhe3/Nherf2 axis in the early adaptive response to MSG-induced renal injury.microPublication biology · 2026Article
- Nherf2 is a major determinant of bile acid pool dynamics and contributes to regulation of Western diet-induced obesity.American journal of physiology. Cell physiology · 2025Article
- Differential regulation of NHE3 expression in type 1 and type 2 diabetic intestine: impaired endosomal regulation of NHE3 expression in type 1 diabetes.American journal of physiology. Cell physiology · 2025Article
- Differential Regulation of NHE3 Expression in Type 1 and Type 2 Diabetic Intestine: Impaired Endosomal Regulation of NHE3 Expression in Type 1 Diabetes.bioRxiv : the preprint server for biology · 2025Article
- Cystinosin is involved in NabioRxiv : the preprint server for biology · 2025Article
- NHERF2 as a Novel Biomarker for Distinguishing MAC Pulmonary Disease from Tuberculosis Based on Proteome Analysis of Serum Extracellular Vesicles.International journal of molecular sciences · 2025Article
- NHERF1/EBP50 immunoexpression in renal cell carcinomas and oncocytomas with ultrastructural analysis of clear cell renal cell carcinoma.Translational andrology and urology · 2023Article
- SLC26A3 (DRA) is stimulated in a synergistic, intracellular CaAmerican journal of physiology. Cell physiology · 2023Article
- mOrange2, a Genetically Encoded, pH Sensitive Fluorescent Protein, is an Alternative to BCECF-AM to Measure Intracellular pH to Determine NHE3 and DRA Activity.Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology · 2022Article
- Identification of Intestinal NaCl Absorptive-Anion Secretory Cells: Potential Functional Significance.Frontiers in physiology · 2022Review
- Altered absorptive function in the gall bladder during cholesterol gallstone formation is associated with abnormal NHE3 complex formation.Journal of physiology and biochemistry · 2020Article
- NHERF3 is necessary forAmerican journal of physiology. Cell physiology · 2019Article
- NHERF1 Is Required for Localization of PMCA2 and Suppression of Early Involution in the Female Lactating Mammary Gland.Endocrinology · 2019Article
- cAMP Stimulates SLC26A3 Activity in Human Colon by a CFTR-Dependent Mechanism That Does Not Require CFTR Activity.Cellular and molecular gastroenterology and hepatology · 2019Article
- Both NHERF3 and NHERF2 are necessary for multiple aspects of acute regulation of NHE3 by elevated CaAmerican journal of physiology. Gastrointestinal and liver physiology · 2018Article
- Regulation of Transporters and Channels by Membrane-Trafficking Complexes in Epithelial Cells.Cold Spring Harbor perspectives in biology · 2017Review
- Phosphorylation of NHE3-SMolecular biology of the cell · 2017Article
- PDZ domain-dependent regulation of NHE3 protein by both internal Class II and C-terminal Class I PDZ-binding motifs.The Journal of biological chemistry · 2017Article
- Phosphorylation and subcellular localization of NaJournal of physiology and biochemistry · 2017Article
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
Abstract
Na(+)/H(+) exchanger 3 (NHE3) is expressed in the brush border (BB) of intestinal epithelial cells and accounts for the majority of neutral NaCl absorption. It has been shown that the Na(+)/H(+) exchanger regulatory factor (NHERF) family members of multi-PDZ domain-containing scaffold proteins bind to the NHE3 COOH terminus and play necessary roles in NHE3 regulation in intestinal epithelial cells. Most studies of NHE3 regulation have been in cell models in which NHERF1 and/or NHERF2 were overexpressed. We have now developed an intestinal Na(+) absorptive cell model in Caco-2/bbe cells by expressing hemagglutinin (HA)-tagged NHE3 with an adenoviral infection system. Roles of NHERF1 and NHERF2 in NHE3 regulation were determined, including inhibition by cAMP, cGMP, and Ca(2+) and stimulation by EGF, with knockdown (KD) approaches with lentivirus (Lenti)-short hairpin RNA (shRNA) and/or adenovirus (Adeno)-small interfering RNA (siRNA). Stable infection of Caco-2/bbe cells by NHERF1 or NHERF2 Lenti-shRNA significantly and specifically reduced NHERF protein expression by >80%. NHERF1 KD reduced basal NHE3 activity, while NHERF2 KD stimulated NHE3 activity. siRNA-mediated (transient) and Lenti-shRNA-mediated (stable) gene silencing of NHERF2 (but not of NHERF1) abolished cGMP- and Ca(2+)-dependent inhibition of NHE3. KD of NHERF1 or NHERF2 alone had no effect on cAMP inhibition of NHE3, but KD of both simultaneously abolished the effect of cAMP. The stimulatory effect of EGF on NHE3 was eliminated in NHERF1-KD but occurred normally in NHERF2-KD cells. These findings show that both NHERF2 and NHERF1 are involved in setting NHE3 activity. NHERF2 is necessary for cGMP-dependent protein kinase (cGK) II- and Ca(2+)-dependent inhibition of NHE3. cAMP-dependent inhibition of NHE3 activity requires either NHERF1 or NHERF2. Stimulation of NHE3 activity by EGF is NHERF1 dependent.
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