CFTR Expression But Not Cl− Transport Is Involved in the Stimulatory Effect of Bile Acids on Apical Cl−/HCO3 − Exchange Activity in Human Pancreatic Duct Cells

Ignáth, Imre; Hegyi, Péter; Venglovecz, Viktória; Székely, Csilla A.; Carr, Georgina; Hasegawa, Mamoru; Inoue, Makoto; Takács, Tamás; Argent, Barry E.; Gray, Michael A.; Rakonczay, Zoltán

doi:10.1097/mpa.0b013e3181b65d34

Cited by 29 publications

(24 citation statements)

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“…Data from the literature are conflicting with respect to the hypothesis that CFTR expression, independently of its transport activity, may be sufficient to activate the expression and/or function of SLC26 transporters [55]. A recent report indicates that CFTR transport activity, and not just its presence, is required for HCO 3 À transport via the SLC26 anion exchangers [44].…”

Section: Discussionmentioning

confidence: 98%

Participation of the Cl−/HCO3− Exchangers SLC26A3 and SLC26A6, the Cl− Channel CFTR, and the Regulatory Factor SLC9A3R1 in Mouse Sperm Capacitation1

Chávez

Hernández‐González

Wertheimer

et al. 2012

Biology of Reproduction

106

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Sperm capacitation is required for fertilization and involves several ion permeability changes. Although Cl(-) and HCO(3)(-) are essential for capacitation, the molecular entities responsible for their transport are not fully known. During mouse sperm capacitation, the intracellular concentration of Cl(-) ([Cl(-)](i)) increases and membrane potential (Em) hyperpolarizes. As in noncapacitated sperm, the Cl(-) equilibrium potential appears to be close to the cell resting Em, opening of Cl(-) channels could not support the [Cl(-)](i) increase observed during capacitation. Alternatively, the [Cl(-)](i) increase might be mediated by anion exchangers. Among them, SLC26A3 and SLC26A6 are good candidates, since, in several cell types, they increase [Cl(-)](i) and interact with cystic fibrosis transmembrane conductance regulator (CFTR), a Cl(-) channel present in mouse and human sperm. This interaction is known to be mediated and probably regulated by the Na(+)/H(+) regulatory factor-1 (official symbol, SLC9A3R1). Our RT-PCR, immunocytochemistry, Western blot, and immunoprecipitation data indicate that SLC26A3, SLC26A6, and SLC9A3R1 are expressed in mouse sperm, localize to the midpiece, and interact between each other and with CFTR. Moreover, we present evidence indicating that CFTR and SLC26A3 are involved in the [Cl(-)](i) increase induced by db-cAMP in noncapacitated sperm. Furthermore, we found that inhibitors of SLC26A3 (Tenidap and 5099) interfere with the Em changes that accompany capacitation. Together, these findings indicate that a CFTR/SLC26A3 functional interaction is important for mouse sperm capacitation.

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Section: Discussionmentioning

confidence: 98%

Participation of the Cl−/HCO3− Exchangers SLC26A3 and SLC26A6, the Cl− Channel CFTR, and the Regulatory Factor SLC9A3R1 in Mouse Sperm Capacitation1

Chávez

Hernández‐González

Wertheimer

et al. 2012

Biology of Reproduction

106

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“…E2F1 controls transcription of multiple genes, each directly or indirectly involved in the regulation of G 1 -S phase entry (cell proliferation) or apoptosis of cells (35,36). E2F1 activation triggered by DNA damage often accompanies with the favorable changes in its chemical modification state and its interaction state with the retinoblastoma protein (37).…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation-regulated miR-193a-3p Dictates Resistance of Hepatocellular Carcinoma to 5-Fluorouracil via Repression of SRSF2 Expression

Zhang

et al. 2012

Journal of Biological Chemistry

104

102

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Background: Chemoresistance prevents effective therapy of hepatocellular carcinoma (HCC). Results: Genomic and mechanistic studies suggested the role of miR-193a-3p via SRSF2 mediates up-regulation of the proapoptotic splicing form of caspase 2 in HCC 5-FU resistance. Conclusion:We identify a novel molecular mechanism underlying 5-FU resistance in HCC. Significance: These molecular events identified provide a set of prognostic markers for future rational 5-FU therapy in HCC.

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“…Furthermore, under experimental conditions, luminal administration of a low dose of chenodeoxycholate (0.1 mM) stimulated ductal HCO 3 − secretion [59] which was caused by significantly elevated apical Cl − /HCO 3 − exchange activity in guinea pig ducts [59] and human CFPAC-1 pancreatic duct cells [60]. This stimulatory effect was dependent on Ca 2+ signaling and CFTR expression; however, it is unlikely to be the result of increased Cl − conductance, since chenodeoxycholate administration did not activate CFTR Cl − channel activity in guinea pig pancreatic duct cells.…”

Section: B Bile Acidsmentioning

confidence: 99%

CFTR: A new horizon in the pathomechanism and treatment of pancreatitis

Hegyi

2016

Pancreatology

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Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that conducts chloride and bicarbonate ions across epithelial cell membranes. Mutations in the CFTR gene diminish the ion channel function and lead to impaired epithelial fluid transport in multiple organs such as the lung and the pancreas resulting in cystic fibrosis. Heterozygous carriers of CFTR mutations do not develop cystic fibrosis but exhibit increased risk for pancreatitis and associated pancreatic damage characterized by elevated mucus levels, fibrosis and cyst formation. Importantly, recent studies demonstrated that pancreatitis causing insults, such as alcohol, smoking or bile acids strongly inhibit CFTR function. Furthermore, human studies showed reduced levels of CFTR expression and function in all forms of pancreatitis. These findings indicate that impairment of CFTR is critical in the development of pancreatitis; therefore, correcting CFTR function could be the first specific therapy in pancreatitis. In this review, we summarize recent advances in the field and discuss new possibilities for the treatment of pancreatitis.Corresponding author: Prof. Dr. Peter Hegyi, Doctor of the Hungarian Academy of Sciences, First Department of Medicine, University of Szeged, Koranyi fsr. 8-10, SZEGED, H6720, Hungary, TEL: +3662545200, FAX: +3662545185, MOBILE: +36703751031, hegyi.peter@med.u-szeged.hu. Conflict of interest statement: the authors have no conflict of interest to declare HHS Public Access I. Basics of CFTR a. Biosynthesis and degradationThe cystic fibrosis transmembrane conductance regulator (CFTR) protein is a cyclic AMP (cAMP)-regulated chloride (Cl − )/bicarbonate (HCO 3 − ) channel, expressed in the apical plasma membrane (PM) of secretory epithelia in the airways, pancreas, intestine, reproductive organs and exocrine glands [1]. CFTR consists of two homologous halves, each containing a hexa-helical membrane spanning domain (MSD1 and MSD2) and a nucleotide binding domain (NBD1 and NBD2) (Figure 1). The two halves are connected by the R domain [2]. The NBDs contain conserved ATP-binding sequences: Walker A and B motifs, classifying CFTR as a member of the ATP-binding cassette (ABC) transporter family. Structural, biochemical and functional evidence suggest that the two NBD domains interact and the ATP-binding site of one NBD is complemented by the ABC signature motif of the other [2].While NBD1 folds largely co-translationally, the native fold of NBD2 as well as CFTR are attained post-translationally [3]. Assembly of MSD1, NBD1, R domain and MSD2 is necessary and sufficient to form the minimal folding unit of CFTR [4]. These and other observations support the cooperative domain folding model and ensure the dynamic conformational coupling between the cytosolic NBDs and the pore-forming MSDs in the native molecule and provide a structural explanation for the cooperative domain unfolding, caused by cystic fibrosis (CF) mutations [4].Despite interactions with several cytosolic and endoplasmic reticulum (ER) chapero...

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CFTR Expression But Not Cl− Transport Is Involved in the Stimulatory Effect of Bile Acids on Apical Cl−/HCO3 − Exchange Activity in Human Pancreatic Duct Cells

Abstract: Bile salts modulate pHi, [Ca(2+)]i, and apical anion exchange activity in human pancreatic duct cells. The stimulatory effect of CDC on anion exchangers requires CFTR expression but not CFTR channel activity.

Cited by 29 publications

References 28 publications

Participation of the Cl−/HCO3− Exchangers SLC26A3 and SLC26A6, the Cl− Channel CFTR, and the Regulatory Factor SLC9A3R1 in Mouse Sperm Capacitation1

Participation of the Cl−/HCO3− Exchangers SLC26A3 and SLC26A6, the Cl− Channel CFTR, and the Regulatory Factor SLC9A3R1 in Mouse Sperm Capacitation1

DNA Methylation-regulated miR-193a-3p Dictates Resistance of Hepatocellular Carcinoma to 5-Fluorouracil via Repression of SRSF2 Expression

CFTR: A new horizon in the pathomechanism and treatment of pancreatitis

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