ArticleProceedings of the National Academy of Sciences of the United States of America2013
Convergence of IRBIT, phosphatidylinositol (4,5) bisphosphate, and WNK/SPAK kinases in regulation of the Na+-HCO3- cotransporters family.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 80 citations in OpenAlex.
- The SLC-ome of membrane transport: from molecular discovery to physiology and clinical applications.Physiological reviews · 2026Review
- Transport mechanism of the SLC4 proteins-Lessons from recent structural and computational studies.The Journal of biological chemistry · 2026Review
- Inactivation mechanisms of NaCommunications biology · 2025Article
- Lipid transporters E-Syt3 and ORP5 regulate epithelial ion transport by controlling phosphatidylserine enrichment at ER/PM junctions.The EMBO journal · 2025Article
- Multiple cAMP/PKA complexes at the STIM1 ER/PM junction specified by E-Syt1 and E-Syt2 reciprocally gates ANO1 (TMEM16A) via CaNature communications · 2025Article
- Rheumatoid arthritis severity is mediated by crosstalk between synoviocytes and mature osteoclasts through a calcium and cytokine feedback loop.Experimental & molecular medicine · 2025Article
- The Bor1 elevator transport cycle is subject to autoinhibition and activation.Nature communications · 2024Article
- The structural insight into the functional modulation of human anion exchanger 3.Nature communications · 2024Article
- Molecular dynamics simulations of lipid-protein interactions in SLC4 proteins.Biophysical journal · 2024Article
- pH regulating mechanisms of astrocytes: A critical component in physiology and disease of the brain.Cell calcium · 2024Review
- Structural and functional insights into the lipid regulation of human anion exchanger 2.Nature communications · 2024Article
- Multiple Regulatory Signals and Components in the Modulation of Bicarbonate Transporters.Pharmaceutics · 2024Review
- SLC26 Anion Transporters.Handbook of experimental pharmacology · 2024Review
- Structural insights into the conformational changes of BTR1/SLC4A11 in complex with PIPNature communications · 2023Article
- Multiple-Factors-Induced Rheumatoid Arthritis Synoviocyte Activation Is Attenuated by the α2-Adrenergic Receptor Agonist Dexmedetomidine.International journal of molecular sciences · 2023Article
- KFrontiers in cellular neuroscience · 2023Article
- Dietary sodium enhances the expression of SLC4 family transporters, IRBIT, L-IRBIT, and PP1 in rat kidney: Insights into the molecular mechanism for renal sodium handling.Frontiers in physiology · 2023Article
- Dynamic synovial fibroblasts are modulated by NBCn1 as a potential target in rheumatoid arthritis.Experimental & molecular medicine · 2022Article
- Review
- Activation of the Ae4 (Slc4a9) cation-driven ClAmerican journal of physiology. Gastrointestinal and liver physiology · 2021Article
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
Abstract
Fluid and HCO3(-) secretion is a vital function of secretory epithelia, involving basolateral HCO3(-) entry through the Na(+)-HCO3(-) cotransporter (NBC) NBCe1-B, and luminal HCO3(-) exit mediated by cystic fibrosis transmembrane conductance regulator (CFTR) and solute carrier family 26 (SLC26) Cl(-)/HCO3(-) exchangers. HCO3(-) secretion is highly regulated, with the WNK/SPAK kinase pathway setting the resting state and the IRBIT/PP1 pathway setting the stimulated state. However, we know little about the relationships between the WNK/SPAK and IRBIT/PP1 sites in the regulation of the transporters. The first 85 N-terminal amino acids of NBCe1-B function as an autoinhibitory domain. Here we have identified a positively charged module within NBCe1-B(37-65) that is conserved in NBCn1-A and all 20 members of the NBC superfamily except NBCe1-A. This module is required for the interaction and activation of NBCe1-B and NBCn1-A by IRBIT and their regulation by phosphatidylinositol 4,5-bisphosphate (PIP2). Activation of the transporters by IRBIT and PIP2 is nonadditive but complementary. Phosphorylation of Ser65 mediates regulation of NBCe1-B by SPAK, and phosphorylation of Thr49 is required for regulation by IRBIT and SPAK. Sequence searches using the NBCe1-B regulatory module as a template identified a homologous sequence in the CFTR R domain and Slc26a6 sulfat transporter and antisigma factor antagonist (STAS) domain. Accordingly, the R and STAS domains bind IRBIT, and the R domain is required for activation of CFTR by IRBIT. These findings reveal convergence of regulatory modalities in a conserved domain of the NBC that may be present in other HCO3(-) transporters and thus in the regulation of epithelial fluid and HCO3(-) secretion.
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