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http://dx.doi.org/10.4196/kjpp.2016.20.4.433

Ahcyl2 upregulates NBCe1-B via multiple serine residues of the PEST domain-mediated association  

Park, Pil Whan (Department of Laboratory Medicine, Gachon University Gil Hospital)
Ahn, Jeong Yeal (Department of Laboratory Medicine, Gachon University Gil Hospital)
Yang, Dongki (Department of Physiology, College of Medicine, Gachon University)
Publication Information
The Korean Journal of Physiology and Pharmacology / v.20, no.4, 2016 , pp. 433-440 More about this Journal
Abstract
Inositol-1,4,5-triphosphate [$IP_3$] receptors binding protein released with $IP_3$ (IRBIT) was previously reported as an activator of NBCe1-B. Recent studies have characterized IRBIT homologue S-Adenosylhomocysteine hydrolase-like 2 (AHCYL2). AHCYL2 is highly homologous to IRBIT (88%) and heteromerizes with IRBIT. The two important domains in the N-terminus of AHCYL2 are a PEST domain and a coiled-coil domain which are highly comparable to those in IRBIT. Therefore, in this study, we tried to identify the role of those domains in mouse AHCYL2 (Ahcyl2), and we succeeded in identifying PEST domain of Ahcyl2 as a regulation region for NBCe1-B activity. Site directed mutagenesis and coimmunoprecipitation assay showed that NBCe1-B binds to the N-terminal Ahcyl2-PEST domain, and its binding is determined by the phosphorylation of 4 critical serine residues (Ser151, Ser154, Ser157, and Ser160) in Ahcyl2 PEST domain. Also we revealed that 4 critical serine residues in Ahcyl2 PEST domain are indispensable for the activation of NBCe1-B using measurement of intracellular pH experiment. Thus, these results suggested that the NBCe1-B is interacted with 4 critical serine residues in Ahcyl2 PEST domain, which play an important role in intracellular pH regulation through NBCe1-B.
Keywords
AHCYL2; $HCO_3{^-}$ secretion; IRBIT; NBCe1-B;
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1 Durie PR. The pathophysiology of the pancreatic defect in cystic fibrosis. Acta Paediatr Scand Suppl. 1989;363:41-44.
2 Baron JH. The pancreas. Mt Sinai J Med. 2000;67:68-75.
3 Steward MC, Ishiguro H, Case RM. Mechanisms of bicarbonate secretion in the pancreatic duct. Annu Rev Physiol. 2005;67:377-409.   DOI
4 Ishiguro H, Steward MC, Lindsay AR, Case RM. Accumulation of intracellular ${HCO_3}^-$ by $Na^+$-${HCO_3}^-$ cotransport in interlobular ducts from guinea-pig pancreas. J Physiol. 1996;495:169-178.   DOI
5 Zhao H, Star RA, Muallem S. Membrane localization of $H^+$ and ${HCO_3}^-$ transporters in the rat pancreatic duct. J Gen Physiol. 1994; 104:57-85.   DOI
6 Abuladze N, Lee I, Newman D, Hwang J, Boorer K, Pushkin A, Kurtz I. Molecular cloning, chromosomal localization, tissue distribution, and functional expression of the human pancreatic sodium bicarbonate cotransporter. J Biol Chem. 1998;273:17689-17695.   DOI
7 Choi JY, Muallem D, Kiselyov K, Lee MG, Thomas PJ, Muallem S. Aberrant CFTR-dependent ${HCO_3}^-$ transport in mutations associated with cystic fibrosis. Nature. 2001;410:94-97.   DOI
8 Ko SB, Shcheynikov N, Choi JY, Luo X, Ishibashi K, Thomas PJ, Kim JY, Kim KH, Lee MG, Naruse S, Muallem S. A molecular mechanism for aberrant CFTR-dependent ${HCO_3}^-$ transport in cystic fibrosis. EMBO J. 2002;21:5662-5672.   DOI
9 Lee MG, Choi JY, Luo X, Strickland E, Thomas PJ, Muallem S. Cystic fibrosis transmembrane conductance regulator regulates luminal $Cl^-$/${HCO_3}^-$ exchange in mouse submandibular and pancreatic ducts. J Biol Chem. 1999;274:14670-14677.   DOI
10 Ko SB, Zeng W, Dorwart MR, Luo X, Kim KH, Millen L, Goto H, Naruse S, Soyombo A, Thomas PJ, Muallem S. Gating of CFTR by the STAS domain of SLC26 transporters. Nat Cell Biol. 2004;6:343-350.   DOI
11 Ando H, Mizutani A, Matsu-ura T, Mikoshiba K. IRBIT, a novel inositol 1,4,5-trisphosphate ($IP_3$) receptor-binding protein, is released from the $IP_3$ receptor upon $IP_3$ binding to the receptor. J Biol Chem. 2003;278:10602-10612.   DOI
12 Shcheynikov N, Ko SB, Zeng W, Choi JY, Dorwart MR, Thomas PJ, Muallem S. Regulatory interaction between CFTR and the SLC26 transporters. Novartis Found Symp. 2006;273:177-186; discussion 186-192, 261-264.
13 Wang Y, Soyombo AA, Shcheynikov N, Zeng W, Dorwart M, Marino CR, Thomas PJ, Muallem S. Slc26a6 regulates CFTR activity in vivo to determine pancreatic duct ${HCO_3}^-$ secretion: relevance to cystic fibrosis. EMBO J. 2006;25:5049-5057.   DOI
14 Dorwart MR, Shcheynikov N, Yang D, Muallem S. The solute carrier 26 family of proteins in epithelial ion transport. Physiology (Bethesda). 2008;23:104-114.   DOI
15 Shirakabe K, Priori G, Yamada H, Ando H, Horita S, Fujita T, Fujimoto I, Mizutani A, Seki G, Mikoshiba K. IRBIT, an inositol 1,4,5-trisphosphate receptor-binding protein, specifically binds to and activates pancreas-type $Na^+$/${HCO_3}^-$ cotransporter 1 (pNBC1). Proc Natl Acad Sci U S A . 2006;103:9542-9547.   DOI
16 Ando H, Mizutani A, Kiefer H, Tsuzurugi D, Michikawa T, Mikoshiba K. IRBIT suppresses $IP_3$ receptor activity by competing with $IP_3$ for the common binding site on the $IP_3$ receptor. Mol Cell. 2006;22:795-806.   DOI
17 Devogelaere B, Beullens M, Sammels E, Derua R, Waelkens E, van Lint J, Parys JB, Missiaen L, Bollen M, De Smedt H. Protein phosphatase-1 is a novel regulator of the interaction between IRBIT and the inositol 1,4,5-trisphosphate receptor. Biochem J. 2007;407:303-311.   DOI
18 Devogelaere B, Sammels E, De Smedt H. The IRBIT domain adds new functions to the AHCY family. Bioessays. 2008;30:642-652.   DOI
19 Yang D, Shcheynikov N, Zeng W, Ohana E, So I, Ando H, Mizutani A, Mikoshiba K, Muallem S. IRBIT coordinates epithelial fluid and ${HCO_3}^-$ secretion by stimulating the transporters pNBC1 and CFTR in the murine pancreatic duct. J Clin Invest. 2009;119:193-202.
20 Hong JH, Yang D, Shcheynikov N, Ohana E, Shin DM, Muallem S. Convergence of IRBIT, phosphatidylinositol (4,5) bisphosphate, and WNK/SPAK kinases in regulation of the $Na^+$-${HCO_3}^-$ cotransporters family. Proc Natl Acad Sci U S A. 2013;110:4105-4110.   DOI
21 Yamaguchi S, Ishikawa T. AHCYL2 (long-IRBIT) as a potential regulator of the electrogenic $Na^+$-${HCO_3}^-$ cotransporter NBCe1-B. FEBS Lett. 2014;588:672-677.   DOI
22 Ando H, Mizutani A, Mikoshiba K. An IRBIT homologue lacks binding activity to inositol 1,4,5-trisphosphate receptor due to the unique N-terminal appendage. J Neurochem. 2009;109:539-550.   DOI
23 Yang D, Li Q, So I, Huang CL, Ando H, Mizutani A, Seki G, Mikoshiba K, Thomas PJ, Muallem S. IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway. J Clin Invest . 2011;121:956-965.   DOI