ArticleThe Journal of biological chemistry2010
NHE3 activity is dependent on direct phosphoinositide binding at the N terminus of its intracellular cytosolic region.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 18 citations in OpenAlex.
- Structural basis of autoinhibition of the human NHE3-CHP1 complex.Science advances · 2022Article
- The intracellular lipid-binding domain of human NaCommunications biology · 2020Article
- Application of Electrophysiology Measurement to Study the Activity of Electro-Neutral Transporters.Journal of visualized experiments : JoVE · 2018Article
- A common NHE3 single-nucleotide polymorphism has normal function and sensitivity to regulatory ligands.American journal of physiology. Gastrointestinal and liver physiology · 2017Article
- Phosphorylation of NHE3-SMolecular biology of the cell · 2017Article
- Nonsynonymous single nucleotide polymorphisms of NHE3 differentially decrease NHE3 transporter activity.American journal of physiology. Cell physiology · 2015Article
- The Na+/H+ Exchanger-3 (NHE3) Activity Requires Ezrin Binding to Phosphoinositide and Its Phosphorylation.PloS one · 2015Article
- AKT and GSK-3 are necessary for direct ezrin binding to NHE3 as part of a C-terminal stimulatory complex: role of a novel Ser-rich NHE3 C-terminal motif in NHE3 activity and trafficking.The Journal of biological chemistry · 2014Article
- Unconventional chemiosmotic coupling of NHA2, a mammalian Na+/H+ antiporter, to a plasma membrane H+ gradient.The Journal of biological chemistry · 2012Article
- Molecular analysis of protein-phosphoinositide interactions.Current topics in microbiology and immunology · 2012Review
- Phosphoinositide binding differentially regulates NHE1 Na+/H+ exchanger-dependent proximal tubule cell survival.The Journal of biological chemistry · 2011Article
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
The small intestinal BB Na(+)/H(+) antiporter NHE3 accounts for the majority of intestinal sodium and water absorption. It is highly regulated with both postprandial inhibition and stimulation sequentially occurring. Phosphatidylinositide 4,5-bisphosphate (PI(4,5)P(2)) and phosphatidylinositide 3,4,5-trisphosphate (PI(3,4,5)P(3)) binding is involved with regulation of multiple transporters. We tested the hypothesis that phosphoinositides bind NHE3 under basal conditions and are necessary for its acute regulation. His(6) proteins were made from the NHE3 C-terminal region divided into four parts as follows: F1 (amino acids 475-589), F2 (amino acids 590-667), F3 (amino acids 668-747), and F4 (amino acids 748-832) and purified by a nickel column. Mutations were made in the F1 region of NHE3 and cloned in pet30a and pcDNA3.1 vectors. PI(4,5)P(2) and PI(3,4,5)P(3) bound only to the NHE3 F1 fusion protein (amino acids 475-589) on liposomal pulldown assays. Mutations were made in the putative lipid binding region of the F1 domain and studied for alterations in lipid binding and Na(+)/H(+) exchange as follows: Y501A/R503A/K505A; F509A/R511A/R512A; R511L/R512L; R520/FR527F; and R551L/R552L. Our results indicate the following. 1) The F1 domain of the NHE3 C terminus has phosphoinositide binding regions. 2) Mutations of these regions alter PI(4,5)P(2) and PI(3,4,5)P(3) binding and basal NHE3 activity. 3) The magnitude of serum stimulation of NHE3 correlates with PI(4,5)P(2) and PI(3,4,5)P(3) binding of NHE3. 4) Wortmannin inhibition of PI3K did not correlate with PI(4,5)P(2) or PI(3,4,5)P(3) binding of NHE3. Two functionally distinct phosphoinositide binding regions (Tyr(501)-Arg(512) and Arg(520)-Arg(552)) are present in the NHE3 F1 domain; both regions are important for serum stimulation, but they display differences in phosphoinositide binding, and the latter but not the former alters NHE3 surface expression.
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