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Convergence of IRBIT, phosphatidylinositol (4,5) bisphosphate, and WNK/SPAK kinases in regulation of the Na+-HCO3− cotransporters family

 Jeong Hee Hong  ;  Dongki Yang  ;  Nikolay Shcheynikov  ;  Ehud Ohana  ;  Dong Min Shin  ;  Shmuel Muallem 
 Proceedings of the National Academy of Sciences of the United States of America, Vol.110(10) : 4105-4110, 2013 
Journal Title
 Proceedings of the National Academy of Sciences of the United States of America 
Issue Date
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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1. Journal Papers (연구논문) > 2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실)
Yonsei Authors
신동민(Shin, Dong Min) ORCID logo https://orcid.org/0000-0001-6042-0435
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