Convergence of IRBIT, phosphatidylinositol (4,5) bisphosphate, and WNK/SPAK kinases in regulation of the Na+-HCO3- cotransporters family
- Authors
- Hong, Jeong Hee; Yang, Dongki; Shcheynikov, Nikolay; Ohana, Ehud; Shin, Dong Min; Muallem, Shmuel
- Issue Date
- Mar-2013
- Publisher
- NATL ACAD SCIENCES
- Citation
- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.110, no.10, pp.4105 - 4110
- Journal Title
- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
- Volume
- 110
- Number
- 10
- Start Page
- 4105
- End Page
- 4110
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/14674
- DOI
- 10.1073/pnas.1221410110
- ISSN
- 0027-8424
- 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 auto-inhibitory 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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