ArticleThe Journal of biological chemistry2015
Cyclic GMP kinase II (cGKII) inhibits NHE3 by altering its trafficking and phosphorylating NHE3 at three required sites: identification of a multifunctional phosphorylation site.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 63 citations in OpenAlex.
- Infectious Diarrhea in Early Childhood across the Global South: Etiologic Diversity and Pathogenic Mechanisms.ACS infectious diseases · 2026Review
- 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
- Gut reactions and gut instincts: regulation of intestinal homeostasis by receptor guanylyl cyclase C (GC-C).The Biochemical journal · 2025Review
- Article
- Congenital diarrhea and enteropathies caused by a heterozygous mutation in theFrontiers in pediatrics · 2025Article
- Incidence rates of resistant enterotoxigenic Escherichia coli in fresh vegetables and salads.Access microbiology · 2025Article
- SPINT2 mutations in the Kunitz domain 2 found in SCSD patients inactivate HAI-2 as prostasin inhibitor via abnormal protein folding and N-glycosylation.Human molecular genetics · 2024Article
- Regulation of the intestinal NaAmerican journal of physiology. Cell physiology · 2024Article
- A Novel Peptide Prevents Enterotoxin- and Inflammation-Induced Intestinal Fluid Secretion by Stimulating Sodium-Hydrogen Exchanger 3 Activity.Gastroenterology · 2023Article
- Article
- The Post-Translational Modification Networking in WNK-Centric Hypertension Regulation and Electrolyte Homeostasis.Biomedicines · 2022Review
- The Role of Plasma Membrane Sodium/Hydrogen Exchangers in Gastrointestinal Functions: Proliferation and Differentiation, Fluid/Electrolyte Transport and Barrier Integrity.Frontiers in physiology · 2022Review
- Receptor Guanylyl Cyclase C and Cyclic GMP in Health and Disease: Perspectives and Therapeutic Opportunities.Frontiers in endocrinology · 2022Review
- Metformin Inhibits NaFrontiers in physiology · 2022Article
- The recycling regulation of sodium-hydrogen exchanger isoform 3(NHE3) in epithelial cells.Cell cycle (Georgetown, Tex.) · 2021Review
- Gut-associated cGMP mediates colitis and dysbiosis in a mouse model of an activating mutation in GUCY2C.The Journal of experimental medicine · 2021Article
- Guanylyl cyclase C as a biomarker for immunotherapies for the treatment of gastrointestinal malignancies.Biomarkers in medicine · 2021Review
- Strategies for cystic fibrosis transmembrane conductance regulator inhibition: from molecular mechanisms to treatment for secretory diarrhoeas.FEBS letters · 2020Review
- Mutational landscape of receptor guanylyl cyclase C: Functional analysis and disease-related mutations.IUBMB life · 2020Review
- NHERF3 is necessary forAmerican journal of physiology. Cell physiology · 2019Article
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
The epithelial brush-border Na(+)/H(+) exchanger NHE3 is acutely inhibited by cGKII/cGMP, but how cGKII inhibits NHE3 is unknown. This study tested the hypothesis that cGMP inhibits NHE3 by phosphorylating it and altering its membrane trafficking. Studies were carried out in PS120/NHERF2 and in Caco-2/Bbe cells overexpressing HA-NHE3 and cGKII, and in mouse ileum. NHE3 activity was measured with 2',7'-bis(carboxyethyl)-S-(and 6)carboxyfluorescein acetoxy methylester/fluorometry. Surface NHE3 was determined by cell surface biotinylation. Identification of NHE3 phosphorylation sites was by iTRAQ/LC-MS/MS with TiO2 enrichment and immunoblotting with specific anti-phospho-NHE3 antibodies. cGMP/cGKII rapidly inhibited NHE3, which was associated with reduced surface NHE3. cGMP/cGKII increased NHE3 phosphorylation at three sites (rabbit Ser(554), Ser(607), and Ser(663), equivalent to mouse Ser(552), Ser(605), and Ser(659)), all of which had to be present at the same time for cGMP to inhibit NHE3. NHE3-Ser(663) phosphorylation was not necessary for cAMP inhibition of NHE3. Dexamethasone (4 h) stimulated wild type NHE3 activity and increased surface expression but failed to stimulate NHE3 activity or increase surface expression when NHE3 was mutated to either S663A or S663D. We conclude that 1) cGMP inhibition of NHE3 is associated with phosphorylation of NHE3 at Ser(554), Ser(607), and Ser(663), all of which are necessary for cGMP/cGKII to inhibit NHE3. 2) Dexamethasone stimulates NHE3 by phosphorylation of a single site, Ser(663). The requirement for three phosphorylation sites in NHE3 for cGKII inhibition, and for phosphorylation of one of these sites for dexamethasone stimulation of NHE3, is a unique example of regulation by phosphorylation.
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