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CFTR functions as a bicarbonate channel in pancreatic duct cells.

Ishiguro H, Steward MC, Naruse S, Ko SB, Goto H, Case RM, Kondo T, Yamamoto A - J. Gen. Physiol. (2009)

Bottom Line: Apical HCO(3)(-) fluxes activated by cyclic AMP were independent of Cl(-) and luminal Na(+), and substantially inhibited by the CFTR blocker, CFTR(inh)-172.From the changes in pH(i), membrane potential, and buffering capacity, the flux and electrochemical gradient of HCO(3)(-) across the apical membrane were determined and used to calculate the HCO(3)(-) permeability.This suggests that CFTR functions as a HCO(3)(-) channel in pancreatic duct cells, and that it provides a significant pathway for HCO(3)(-) transport across the apical membrane.

View Article: PubMed Central - PubMed

Affiliation: Human Nutrition, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. ishiguro@htc.nagoya-u.ac.jp

ABSTRACT
Pancreatic duct epithelium secretes a HCO(3)(-)-rich fluid by a mechanism dependent on cystic fibrosis transmembrane conductance regulator (CFTR) in the apical membrane. However, the exact role of CFTR remains unclear. One possibility is that the HCO(3)(-) permeability of CFTR provides a pathway for apical HCO(3)(-) efflux during maximal secretion. We have therefore attempted to measure electrodiffusive fluxes of HCO(3)(-) induced by changes in membrane potential across the apical membrane of interlobular ducts isolated from the guinea pig pancreas. This was done by recording the changes in intracellular pH (pH(i)) that occurred in luminally perfused ducts when membrane potential was altered by manipulation of bath K(+) concentration. Apical HCO(3)(-) fluxes activated by cyclic AMP were independent of Cl(-) and luminal Na(+), and substantially inhibited by the CFTR blocker, CFTR(inh)-172. Furthermore, comparable HCO(3)(-) fluxes observed in ducts isolated from wild-type mice were absent in ducts from cystic fibrosis (Delta F) mice. To estimate the HCO(3)(-) permeability of the apical membrane under physiological conditions, guinea pig ducts were luminally perfused with a solution containing 125 mM HCO(3)(-) and 24 mM Cl(-) in the presence of 5% CO(2). From the changes in pH(i), membrane potential, and buffering capacity, the flux and electrochemical gradient of HCO(3)(-) across the apical membrane were determined and used to calculate the HCO(3)(-) permeability. Our estimate of approximately 0.1 microm sec(-1) for the apical HCO(3)(-) permeability of guinea pig duct cells under these conditions is close to the value required to account for observed rates of HCO(3)(-) secretion. This suggests that CFTR functions as a HCO(3)(-) channel in pancreatic duct cells, and that it provides a significant pathway for HCO(3)(-) transport across the apical membrane.

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HCO3− fluxes across the apical membrane of interlobular pancreatic ducts isolated from wild-type and ΔF mice. Membrane potential–evoked changes in pHi in interlobular pancreatic ducts isolated from wild-type (A) and ΔF/ΔF (B) mice. Experiments were performed in the bilateral absence of Cl− following a similar protocol to that used in the guinea pig duct experiment shown in Fig. 2 A. Each trace is a representative of four experiments.
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fig4: HCO3− fluxes across the apical membrane of interlobular pancreatic ducts isolated from wild-type and ΔF mice. Membrane potential–evoked changes in pHi in interlobular pancreatic ducts isolated from wild-type (A) and ΔF/ΔF (B) mice. Experiments were performed in the bilateral absence of Cl− following a similar protocol to that used in the guinea pig duct experiment shown in Fig. 2 A. Each trace is a representative of four experiments.

Mentions: In ducts isolated from wild-type mice, membrane hyperpolarization and depolarization evoked by lowering and raising [K+]B caused decreases and increases in pHi (Fig. 4 A), which were similar to those observed in the guinea pig ducts. In ducts isolated from the ΔF mice (Fig. 4 B), however, these changes in pHi were almost entirely abolished. This result strongly supports the conclusion that, in mice at least, the electrodiffusive fluxes of HCO3− that we have observed across the apical membrane are carried largely by CFTR.


CFTR functions as a bicarbonate channel in pancreatic duct cells.

Ishiguro H, Steward MC, Naruse S, Ko SB, Goto H, Case RM, Kondo T, Yamamoto A - J. Gen. Physiol. (2009)

HCO3− fluxes across the apical membrane of interlobular pancreatic ducts isolated from wild-type and ΔF mice. Membrane potential–evoked changes in pHi in interlobular pancreatic ducts isolated from wild-type (A) and ΔF/ΔF (B) mice. Experiments were performed in the bilateral absence of Cl− following a similar protocol to that used in the guinea pig duct experiment shown in Fig. 2 A. Each trace is a representative of four experiments.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2654087&req=5

fig4: HCO3− fluxes across the apical membrane of interlobular pancreatic ducts isolated from wild-type and ΔF mice. Membrane potential–evoked changes in pHi in interlobular pancreatic ducts isolated from wild-type (A) and ΔF/ΔF (B) mice. Experiments were performed in the bilateral absence of Cl− following a similar protocol to that used in the guinea pig duct experiment shown in Fig. 2 A. Each trace is a representative of four experiments.
Mentions: In ducts isolated from wild-type mice, membrane hyperpolarization and depolarization evoked by lowering and raising [K+]B caused decreases and increases in pHi (Fig. 4 A), which were similar to those observed in the guinea pig ducts. In ducts isolated from the ΔF mice (Fig. 4 B), however, these changes in pHi were almost entirely abolished. This result strongly supports the conclusion that, in mice at least, the electrodiffusive fluxes of HCO3− that we have observed across the apical membrane are carried largely by CFTR.

Bottom Line: Apical HCO(3)(-) fluxes activated by cyclic AMP were independent of Cl(-) and luminal Na(+), and substantially inhibited by the CFTR blocker, CFTR(inh)-172.From the changes in pH(i), membrane potential, and buffering capacity, the flux and electrochemical gradient of HCO(3)(-) across the apical membrane were determined and used to calculate the HCO(3)(-) permeability.This suggests that CFTR functions as a HCO(3)(-) channel in pancreatic duct cells, and that it provides a significant pathway for HCO(3)(-) transport across the apical membrane.

View Article: PubMed Central - PubMed

Affiliation: Human Nutrition, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. ishiguro@htc.nagoya-u.ac.jp

ABSTRACT
Pancreatic duct epithelium secretes a HCO(3)(-)-rich fluid by a mechanism dependent on cystic fibrosis transmembrane conductance regulator (CFTR) in the apical membrane. However, the exact role of CFTR remains unclear. One possibility is that the HCO(3)(-) permeability of CFTR provides a pathway for apical HCO(3)(-) efflux during maximal secretion. We have therefore attempted to measure electrodiffusive fluxes of HCO(3)(-) induced by changes in membrane potential across the apical membrane of interlobular ducts isolated from the guinea pig pancreas. This was done by recording the changes in intracellular pH (pH(i)) that occurred in luminally perfused ducts when membrane potential was altered by manipulation of bath K(+) concentration. Apical HCO(3)(-) fluxes activated by cyclic AMP were independent of Cl(-) and luminal Na(+), and substantially inhibited by the CFTR blocker, CFTR(inh)-172. Furthermore, comparable HCO(3)(-) fluxes observed in ducts isolated from wild-type mice were absent in ducts from cystic fibrosis (Delta F) mice. To estimate the HCO(3)(-) permeability of the apical membrane under physiological conditions, guinea pig ducts were luminally perfused with a solution containing 125 mM HCO(3)(-) and 24 mM Cl(-) in the presence of 5% CO(2). From the changes in pH(i), membrane potential, and buffering capacity, the flux and electrochemical gradient of HCO(3)(-) across the apical membrane were determined and used to calculate the HCO(3)(-) permeability. Our estimate of approximately 0.1 microm sec(-1) for the apical HCO(3)(-) permeability of guinea pig duct cells under these conditions is close to the value required to account for observed rates of HCO(3)(-) secretion. This suggests that CFTR functions as a HCO(3)(-) channel in pancreatic duct cells, and that it provides a significant pathway for HCO(3)(-) transport across the apical membrane.

Show MeSH
Related in: MedlinePlus