Bicarbonate-rich fluid secretion predicted by a computational model of guinea-pig pancreatic duct epithelium

Makoto Yamaguchi, Martin C. Steward, Kieran Smallbone, Yoshiro Sohma, Akiko Yamamoto, Shigeru Ko, Takaharu Kondo, Hiroshi Ishiguro

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Key points: The ductal system of the pancreas secretes large volumes of alkaline fluid containing HCO3 - concentrations as high as 140 mm during hormonal stimulation. A computational model has been constructed to explore the underlying ion transport mechanisms. Parameters were estimated by fitting the model to experimental data from guinea-pig pancreatic ducts. The model was readily able to secrete 140 mm HCO3 -. Its capacity to do so was not dependent upon special properties of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channels and solute carrier family 26 member A6 (SLC26A6) anion exchangers. We conclude that the main requirement for secreting high HCO3 - concentrations is to minimize the secretion of Cl- ions. These findings help to clarify the mechanism responsible for pancreatic HCO3 - secretion, a vital process that prevents the formation of protein plugs and viscous mucus in the ducts, which could otherwise lead to pancreatic disease. A computational model of guinea-pig pancreatic duct epithelium was developed to determine the transport mechanism by which HCO3 - ions are secreted at concentrations in excess of 140 mm. Parameters defining the contributions of the individual ion channels and transporters were estimated by least-squares fitting of the model predictions to experimental data obtained from isolated ducts and intact pancreas under a range of experimental conditions. The effects of cAMP-stimulated secretion were well replicated by increasing the activities of the basolateral Na+-HCO3 - cotransporter (NBC1) and apical Cl-/HCO3 - exchanger (solute carrier family 26 member A6; SLC26A6), increasing the basolateral K+ permeability and apical Cl- and HCO3 - permeabilities (CFTR), and reducing the activity of the basolateral Cl-/HCO3 - exchanger (anion exchanger 2; AE2). Under these conditions, the model secreted ∼140 mm HCO3 - at a rate of ∼3 nl min-1 mm-2, which is consistent with experimental observations. Alternative 1:2 and 1:1 stoichiometries for Cl-/HCO3 - exchange via SLC26A6 at the apical membrane were able to support a HCO3 --rich secretion. Raising the HCO3 -/Cl- permeability ratio of CFTR from 0.4 to 1.0 had little impact upon either the secreted HCO3 - concentration or the volume flow. However, modelling showed that a reduction in basolateral AE2 activity by ∼80% was essential in minimizing the intracellular Cl- concentration following cAMP stimulation and thereby maximizing the secreted HCO3 - concentration. The addition of a basolateral Na+-K+-2Cl- cotransporter (NKCC1), assumed to be present in rat and mouse ducts, raised intracellular Cl- and resulted in a lower secreted HCO3 - concentration, as is characteristic of those species. We conclude therefore that minimizing the driving force for Cl- secretion is the main requirement for secreting 140 mm HCO3 -.

Original languageEnglish
JournalJournal of Physiology
DOIs
Publication statusAccepted/In press - 2017

Fingerprint

Fluids and Secretions
Pancreatic Ducts
Chloride-Bicarbonate Antiporters
Bicarbonates
Cystic Fibrosis Transmembrane Conductance Regulator
Guinea Pigs
Epithelium
Permeability
Anions
Pancreas
Member 2 Solute Carrier Family 12
Ions
Pancreatic Diseases
Ion Transport
Mucus
Least-Squares Analysis
Ion Channels
Theoretical Models
Membranes
Proteins

Keywords

  • Bicarbonate secretion
  • Computational model
  • Pancreatic duct

ASJC Scopus subject areas

  • Physiology

Cite this

Yamaguchi, M., Steward, M. C., Smallbone, K., Sohma, Y., Yamamoto, A., Ko, S., ... Ishiguro, H. (Accepted/In press). Bicarbonate-rich fluid secretion predicted by a computational model of guinea-pig pancreatic duct epithelium. Journal of Physiology. https://doi.org/10.1113/JP273306

Bicarbonate-rich fluid secretion predicted by a computational model of guinea-pig pancreatic duct epithelium. / Yamaguchi, Makoto; Steward, Martin C.; Smallbone, Kieran; Sohma, Yoshiro; Yamamoto, Akiko; Ko, Shigeru; Kondo, Takaharu; Ishiguro, Hiroshi.

In: Journal of Physiology, 2017.

Research output: Contribution to journalArticle

Yamaguchi, Makoto ; Steward, Martin C. ; Smallbone, Kieran ; Sohma, Yoshiro ; Yamamoto, Akiko ; Ko, Shigeru ; Kondo, Takaharu ; Ishiguro, Hiroshi. / Bicarbonate-rich fluid secretion predicted by a computational model of guinea-pig pancreatic duct epithelium. In: Journal of Physiology. 2017.
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AU - Yamaguchi, Makoto

AU - Steward, Martin C.

AU - Smallbone, Kieran

AU - Sohma, Yoshiro

AU - Yamamoto, Akiko

AU - Ko, Shigeru

AU - Kondo, Takaharu

AU - Ishiguro, Hiroshi

PY - 2017

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N2 - Key points: The ductal system of the pancreas secretes large volumes of alkaline fluid containing HCO3 - concentrations as high as 140 mm during hormonal stimulation. A computational model has been constructed to explore the underlying ion transport mechanisms. Parameters were estimated by fitting the model to experimental data from guinea-pig pancreatic ducts. The model was readily able to secrete 140 mm HCO3 -. Its capacity to do so was not dependent upon special properties of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channels and solute carrier family 26 member A6 (SLC26A6) anion exchangers. We conclude that the main requirement for secreting high HCO3 - concentrations is to minimize the secretion of Cl- ions. These findings help to clarify the mechanism responsible for pancreatic HCO3 - secretion, a vital process that prevents the formation of protein plugs and viscous mucus in the ducts, which could otherwise lead to pancreatic disease. A computational model of guinea-pig pancreatic duct epithelium was developed to determine the transport mechanism by which HCO3 - ions are secreted at concentrations in excess of 140 mm. Parameters defining the contributions of the individual ion channels and transporters were estimated by least-squares fitting of the model predictions to experimental data obtained from isolated ducts and intact pancreas under a range of experimental conditions. The effects of cAMP-stimulated secretion were well replicated by increasing the activities of the basolateral Na+-HCO3 - cotransporter (NBC1) and apical Cl-/HCO3 - exchanger (solute carrier family 26 member A6; SLC26A6), increasing the basolateral K+ permeability and apical Cl- and HCO3 - permeabilities (CFTR), and reducing the activity of the basolateral Cl-/HCO3 - exchanger (anion exchanger 2; AE2). Under these conditions, the model secreted ∼140 mm HCO3 - at a rate of ∼3 nl min-1 mm-2, which is consistent with experimental observations. Alternative 1:2 and 1:1 stoichiometries for Cl-/HCO3 - exchange via SLC26A6 at the apical membrane were able to support a HCO3 --rich secretion. Raising the HCO3 -/Cl- permeability ratio of CFTR from 0.4 to 1.0 had little impact upon either the secreted HCO3 - concentration or the volume flow. However, modelling showed that a reduction in basolateral AE2 activity by ∼80% was essential in minimizing the intracellular Cl- concentration following cAMP stimulation and thereby maximizing the secreted HCO3 - concentration. The addition of a basolateral Na+-K+-2Cl- cotransporter (NKCC1), assumed to be present in rat and mouse ducts, raised intracellular Cl- and resulted in a lower secreted HCO3 - concentration, as is characteristic of those species. We conclude therefore that minimizing the driving force for Cl- secretion is the main requirement for secreting 140 mm HCO3 -.

AB - Key points: The ductal system of the pancreas secretes large volumes of alkaline fluid containing HCO3 - concentrations as high as 140 mm during hormonal stimulation. A computational model has been constructed to explore the underlying ion transport mechanisms. Parameters were estimated by fitting the model to experimental data from guinea-pig pancreatic ducts. The model was readily able to secrete 140 mm HCO3 -. Its capacity to do so was not dependent upon special properties of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channels and solute carrier family 26 member A6 (SLC26A6) anion exchangers. We conclude that the main requirement for secreting high HCO3 - concentrations is to minimize the secretion of Cl- ions. These findings help to clarify the mechanism responsible for pancreatic HCO3 - secretion, a vital process that prevents the formation of protein plugs and viscous mucus in the ducts, which could otherwise lead to pancreatic disease. A computational model of guinea-pig pancreatic duct epithelium was developed to determine the transport mechanism by which HCO3 - ions are secreted at concentrations in excess of 140 mm. Parameters defining the contributions of the individual ion channels and transporters were estimated by least-squares fitting of the model predictions to experimental data obtained from isolated ducts and intact pancreas under a range of experimental conditions. The effects of cAMP-stimulated secretion were well replicated by increasing the activities of the basolateral Na+-HCO3 - cotransporter (NBC1) and apical Cl-/HCO3 - exchanger (solute carrier family 26 member A6; SLC26A6), increasing the basolateral K+ permeability and apical Cl- and HCO3 - permeabilities (CFTR), and reducing the activity of the basolateral Cl-/HCO3 - exchanger (anion exchanger 2; AE2). Under these conditions, the model secreted ∼140 mm HCO3 - at a rate of ∼3 nl min-1 mm-2, which is consistent with experimental observations. Alternative 1:2 and 1:1 stoichiometries for Cl-/HCO3 - exchange via SLC26A6 at the apical membrane were able to support a HCO3 --rich secretion. Raising the HCO3 -/Cl- permeability ratio of CFTR from 0.4 to 1.0 had little impact upon either the secreted HCO3 - concentration or the volume flow. However, modelling showed that a reduction in basolateral AE2 activity by ∼80% was essential in minimizing the intracellular Cl- concentration following cAMP stimulation and thereby maximizing the secreted HCO3 - concentration. The addition of a basolateral Na+-K+-2Cl- cotransporter (NKCC1), assumed to be present in rat and mouse ducts, raised intracellular Cl- and resulted in a lower secreted HCO3 - concentration, as is characteristic of those species. We conclude therefore that minimizing the driving force for Cl- secretion is the main requirement for secreting 140 mm HCO3 -.

KW - Bicarbonate secretion

KW - Computational model

KW - Pancreatic duct

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