Cystic Fibrosis Transmembrane Conductance Regulator Regulates Luminal Cl−/HCO3−Exchange in Mouse Submandibular and Pancreatic Ducts

Lee, Min Goo; Choi, Joo Young; Luo, Xiang; Strickland, Elizabeth; Thomas, Philip; Muallem, Shmuel

doi:10.1074/jbc.274.21.14670

Cited by 179 publications

(151 citation statements)

References 45 publications

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“…3, B-D). We conclude that gpSlc26a3 mediates predominantly electroneutral Cl Ϫ /HCO 3 Ϫ exchange, in concert with data reported for human SLC26A3 (8) and mouse Slc26a3 (1,17,26,28,31,58,59). However, functional data on microperfused isolated interlobular ducts suggests that Slc26a3-like, H 2 -DIDS-insensitive Cl Ϫ /HCO 3 Ϫ exchange constitutes only ϳ20% of apical Cl Ϫ /HCO 3 Ϫ exchange under alkaline load conditions (53).…”

Section: C297mentioning

confidence: 42%

SLC26 anion exchangers of guinea pig pancreatic duct: molecular cloning and functional characterization

Stewart

Shmukler

Vandorpe

et al. 2011

American Journal of Physiology-Cell Physiology

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The secretin-stimulated human pancreatic duct secretes HCO3−-rich fluid essential for normal digestion. Optimal stimulation of pancreatic HCO3− secretion likely requires coupled activities of the cystic fibrosis transmembrane regulator (CFTR) anion channel and apical SLC26 Cl−/HCO3− exchangers. However, whereas stimulated human and guinea pig pancreatic ducts secrete ∼140 mM HCO3− or more, mouse and rat ducts secrete ∼40–70 mM HCO3−. Moreover, the axial distribution and physiological roles of SLC26 anion exchangers in pancreatic duct secretory processes remain controversial and may vary among mammalian species. Thus the property of high HCO3− secretion shared by human and guinea pig pancreatic ducts prompted us to clone from guinea pig pancreatic duct cDNAs encoding Slc26a3, Slc26a6, and Slc26a11 polypeptides. We then functionally characterized these anion transporters in Xenopus oocytes and human embryonic kidney (HEK) 293 cells. In Xenopus oocytes, gpSlc26a3 mediated only Cl−/Cl− exchange and electroneutral Cl−/HCO3− exchange. gpSlc26a6 in Xenopus oocytes mediated Cl−/Cl− exchange and bidirectional exchange of Cl− for oxalate and sulfate, but Cl−/HCO3− exchange was detected only in HEK 293 cells. gpSlc26a11 in Xenopus oocytes exhibited pH-dependent Cl−, oxalate, and sulfate transport but no detectable Cl−/HCO3− exchange. The three gpSlc26 anion transporters exhibited distinct pharmacological profiles of 36Cl− influx, including partial sensitivity to CFTR inhibitors Inh-172 and GlyH101, but only Slc26a11 was inhibited by PPQ-102. This first molecular and functional assessment of recombinant SLC26 anion transporters from guinea pig pancreatic duct enhances our understanding of pancreatic HCO3− secretion in species that share a high HCO3− secretory output.

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Section: C297mentioning

confidence: 42%

SLC26 anion exchangers of guinea pig pancreatic duct: molecular cloning and functional characterization

Stewart

Shmukler

Vandorpe

et al. 2011

American Journal of Physiology-Cell Physiology

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“…This would be similar to the pathology seen in the pancreas of CFTR mutant mice where defects in chloride transport in the duct epithelium results in lack of fluid secretion and premature activation of pancreatic digestive enzymes. [85][86][87] Alternatively, there may be an unidentified signaling pathway between the ducts and acini required for acinar cell survival, maintenance, or regulation of zymogen granule release.…”

Section: Discussionmentioning

confidence: 99%

Disruption of IFT results in both exocrine and endocrine abnormalities in the pancreas of Tg737 mutant mice

Zhang

Davenport

Croyle

et al. 2005

Laboratory Investigation

100

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While relatively ignored for years as vestigial, cilia have recently become the focus of intense interest as organelles that result in severe pathologies when disrupted. Here, we further establish a connection between cilia dysfunction and disease by showing that loss of polaris (Tg737), an intraflagellar transport (IFT) protein required for ciliogenesis, causes abnormalities in the exocrine and endocrine pancreas of the Tg737 orpk mouse. Pathology is evident late in gestation as dilatations of the pancreatic ducts that continue to expand postnatally. Shortly after birth, the acini become disorganized, undergo apoptosis, and are largely ablated in late stage pathology. In addition, serum amylase levels are elevated and carboxypeptidase is abnormally activated within the pancreas. Ultrastructural analysis reveals that the acini undergo extensive vacuolization and have numerous 'halo-granules' similar to that seen in induced models of pancreatitis resulting from duct obstruction. Intriguingly, although the acini are severely affected in Tg737 orpk mutants, cilia and Tg737 expression are restricted to the ducts and islets and are not detected on acinar cells. Analysis of the endocrine pancreas in Tg737 orpk mutants revealed normal differentiation and distribution of cell types in the islets. However, after fasting, mutant blood glucose levels are significantly lower than controls and when challenged in glucose tolerance tests, Tg737 orpk mutants exhibited defects in glucose uptake. These findings are interesting in light of the recently proposed role for polaris, the protein encoded by the Tg737 gene, in the hedgehog pathway and hedgehog signaling in insulin production and glucose homeostasis.

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“…This suggests that CFTR may have other functions, besides conducting Cl Ϫ , that are essential for normal fluid and electrolyte transport. Indeed, CFTR regulates the activity of the epithelial Na ϩ channel ENaC (4), and CFTR supports Cl Ϫ /HCO 3 Ϫ exchange activity in heterologous expression systems (5) and in the mouse pancreatic duct (6). Importantly, aberrant HCO 3 Ϫ transport in cells expressing CFTR mutants that retain Cl Ϫ channel activity correlates with the pancreatic status of the CF phenotype (7).…”

Section: Patients (1) Cf Is Caused By Mutations In the Cystic Fibrosmentioning

confidence: 99%

Regulatory Interaction between the Cystic Fibrosis Transmembrane Conductance Regulator and HCO 3− Salvage Mechanisms in Model Systems and the Mouse Pancreatic Duct

Ahn

Kim

Lee

et al. 2001

Journal of Biological Chemistry

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104

114

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The pancreatic duct expresses cystic fibrosis transmembrane conductance regulator (CFTR) and HCO 3 ؊ secretory and salvage mechanisms in the luminal membrane. Although CFTR plays a prominent role in HCO 3 ؊ secretion, the role of CFTR in HCO 3 ؊ salvage is not known. In the present work, we used molecular, biochemical, and functional approaches to study the regulatory interaction between CFTR and the HCO 3 ؊ salvage mechanism Na ؉ /H ؉ exchanger isoform 3 (NHE3) in heterologous expression systems and in the native pancreatic duct. We found that CFTR regulates NHE3 activity by both acute and chronic mechanisms. In the pancreatic duct, CFTR increases expression of NHE3 in the luminal membrane. Thus, luminal expression of NHE3 was reduced by 53% in ducts of homozygote ⌬F508 mice. Accordingly, luminal Na ؉ -dependent and HOE694-sensitive recovery from an acid load was reduced by 60% in ducts of ⌬F508 mice. CFTR and NHE3 were coimmunoprecipitated from PS120 cells expressing both proteins and the pancreatic duct of wild type mice but not from PS120 cells lacking CFTR or the pancreas of ⌬F508 mice. The interaction between CFTR and NHE3 required the COOH-terminal PDZ binding motif of CFTR, and mutant CFTR proteins lacking the C terminus were not co-immunoprecipitated with NHE3. Furthermore, when expressed in PS120 cells, wild type CFTR, but not CFTR mutants lacking the C-terminal PDZ binding motif, augmented cAMP-dependent inhibition of NHE3 activity by 31%. These findings reveal that CFTR controls overall HCO 3 ؊ homeostasis by regulating both pancreatic ductal HCO 3 ؊ secretory and salvage mechanisms.Fluid secretion and the control of the ionic composition of biological fluids are essential for the function of many secretory epithelia, including the respiratory, digestive, and reproductive systems. HCO 3 Ϫ is an important constituent of secreted fluids by virtue of its function as the biological pH buffer and its effect on the solubility of proteins and ions in biological fluids. Accordingly, the mechanisms underlying HCO 3 Ϫ homeostasis at rest and during stimulation have attracted much attention in recent years. The importance of HCO 3 Ϫ homeostasis is evident from the marked reduction in Cl Ϫ -and HCO 3 Ϫ

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Cystic Fibrosis Transmembrane Conductance Regulator Regulates Luminal Cl−/HCO3−Exchange in Mouse Submandibular and Pancreatic Ducts

Cited by 179 publications

References 45 publications

SLC26 anion exchangers of guinea pig pancreatic duct: molecular cloning and functional characterization

SLC26 anion exchangers of guinea pig pancreatic duct: molecular cloning and functional characterization

Disruption of IFT results in both exocrine and endocrine abnormalities in the pancreas of Tg737 mutant mice

Regulatory Interaction between the Cystic Fibrosis Transmembrane Conductance Regulator and HCO 3− Salvage Mechanisms in Model Systems and the Mouse Pancreatic Duct

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