SLC26 Transporters and the Inhibitory Control of Pancreatic Ductal Bicarbonate Secretion

P. Hegyi, Z. Rakonczay, L. Tiszlavicz, A. Varró, A. Tóth, Gábor Rácz, G. Varga, Michael A. Gray, Barry E. Argent

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

SLC26 anion exchangers (probably SLC26A3 and SLC26A6) are expressed on the apical membrane of pancreatic duct cells and play a key role in HCO3- secretion; process that is inhibited by the neuropeptide, substance P (SP). SP had no effect on basolateral HCO3- transporters in the duct cell or on CFTR Cl- channels, but inhibited a Cl--dependent HCO3- efflux step on the apical membrane. In microperfused ducts, luminal H2DIDS (0.5 mM) caused intracellular pH to alkalinize (consistent with inhibition of HCO3- efflux) and, like SP, inhibited HCO3- secretion. SP did not reduce HCO3- secretion further when H2DIDS was applied to the duct lumen, suggesting that SP and H2DIDS inhibit the same transporter on the apical membrane. As SLC26A6 is DIDS-sensitive, this isoform is the likely target for SP. The inhibitory effect of SP was mimicked by phorbol 12,13-dibutyrate (PDBu), an activator of protein kinase C (PKC). Moreover, bisindolylmaleimide, a blocker of PKC, relieved the inhibitory effect of both SP and PDBu on HCO3- secretion. Western blot analysis revealed that guinea pig pancreatic ducts express the α, β1, δ, ε, η, θ, ζ and μ isoforms of PKC. We conclude that PKC is negative regulator of SLC26 activity in pancreatic duct cells.

Original languageEnglish
Title of host publicationEpithelial Anion Transport in Health and Disease: The Role of the SLC26 Transporters Family
PublisherWiley Blackwell
Pages164-173
Number of pages10
ISBN (Print)9780470029572, 0470016248, 9780470016244
DOIs
Publication statusPublished - Oct 7 2008

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Substance P
Bicarbonates
Ducts
Protein Kinase C
Pancreatic Ducts
Phorbol 12,13-Dibutyrate
Membranes
Protein Isoforms
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid
Neuropeptides
Anions
Guinea Pigs
Western Blotting
dihydro-DIDS

Keywords

  • 'alkali load' method and assessing NKCCs
  • 'inhibitor stop' method
  • Inhibition of Cl--dependent HCO3- efflux step
  • PDZK1 knockout and missing SLC26A6
  • PKC inhibiting SLC26 transporters in pancreatic duct
  • SLC26 anion exchangers in HCO3- secretion
  • SLC26 anion exchangers of pancreatic duct cells
  • SLC26A6 as DIDS-sensitive

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Hegyi, P., Rakonczay, Z., Tiszlavicz, L., Varró, A., Tóth, A., Rácz, G., ... Argent, B. E. (2008). SLC26 Transporters and the Inhibitory Control of Pancreatic Ductal Bicarbonate Secretion. In Epithelial Anion Transport in Health and Disease: The Role of the SLC26 Transporters Family (pp. 164-173). Wiley Blackwell. https://doi.org/10.1002/0470029579.ch11

SLC26 Transporters and the Inhibitory Control of Pancreatic Ductal Bicarbonate Secretion. / Hegyi, P.; Rakonczay, Z.; Tiszlavicz, L.; Varró, A.; Tóth, A.; Rácz, Gábor; Varga, G.; Gray, Michael A.; Argent, Barry E.

Epithelial Anion Transport in Health and Disease: The Role of the SLC26 Transporters Family. Wiley Blackwell, 2008. p. 164-173.

Research output: Chapter in Book/Report/Conference proceedingChapter

Hegyi, P, Rakonczay, Z, Tiszlavicz, L, Varró, A, Tóth, A, Rácz, G, Varga, G, Gray, MA & Argent, BE 2008, SLC26 Transporters and the Inhibitory Control of Pancreatic Ductal Bicarbonate Secretion. in Epithelial Anion Transport in Health and Disease: The Role of the SLC26 Transporters Family. Wiley Blackwell, pp. 164-173. https://doi.org/10.1002/0470029579.ch11
Hegyi P, Rakonczay Z, Tiszlavicz L, Varró A, Tóth A, Rácz G et al. SLC26 Transporters and the Inhibitory Control of Pancreatic Ductal Bicarbonate Secretion. In Epithelial Anion Transport in Health and Disease: The Role of the SLC26 Transporters Family. Wiley Blackwell. 2008. p. 164-173 https://doi.org/10.1002/0470029579.ch11
Hegyi, P. ; Rakonczay, Z. ; Tiszlavicz, L. ; Varró, A. ; Tóth, A. ; Rácz, Gábor ; Varga, G. ; Gray, Michael A. ; Argent, Barry E. / SLC26 Transporters and the Inhibitory Control of Pancreatic Ductal Bicarbonate Secretion. Epithelial Anion Transport in Health and Disease: The Role of the SLC26 Transporters Family. Wiley Blackwell, 2008. pp. 164-173
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AU - Hegyi, P.

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AU - Varró, A.

AU - Tóth, A.

AU - Rácz, Gábor

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AU - Gray, Michael A.

AU - Argent, Barry E.

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N2 - SLC26 anion exchangers (probably SLC26A3 and SLC26A6) are expressed on the apical membrane of pancreatic duct cells and play a key role in HCO3- secretion; process that is inhibited by the neuropeptide, substance P (SP). SP had no effect on basolateral HCO3- transporters in the duct cell or on CFTR Cl- channels, but inhibited a Cl--dependent HCO3- efflux step on the apical membrane. In microperfused ducts, luminal H2DIDS (0.5 mM) caused intracellular pH to alkalinize (consistent with inhibition of HCO3- efflux) and, like SP, inhibited HCO3- secretion. SP did not reduce HCO3- secretion further when H2DIDS was applied to the duct lumen, suggesting that SP and H2DIDS inhibit the same transporter on the apical membrane. As SLC26A6 is DIDS-sensitive, this isoform is the likely target for SP. The inhibitory effect of SP was mimicked by phorbol 12,13-dibutyrate (PDBu), an activator of protein kinase C (PKC). Moreover, bisindolylmaleimide, a blocker of PKC, relieved the inhibitory effect of both SP and PDBu on HCO3- secretion. Western blot analysis revealed that guinea pig pancreatic ducts express the α, β1, δ, ε, η, θ, ζ and μ isoforms of PKC. We conclude that PKC is negative regulator of SLC26 activity in pancreatic duct cells.

AB - SLC26 anion exchangers (probably SLC26A3 and SLC26A6) are expressed on the apical membrane of pancreatic duct cells and play a key role in HCO3- secretion; process that is inhibited by the neuropeptide, substance P (SP). SP had no effect on basolateral HCO3- transporters in the duct cell or on CFTR Cl- channels, but inhibited a Cl--dependent HCO3- efflux step on the apical membrane. In microperfused ducts, luminal H2DIDS (0.5 mM) caused intracellular pH to alkalinize (consistent with inhibition of HCO3- efflux) and, like SP, inhibited HCO3- secretion. SP did not reduce HCO3- secretion further when H2DIDS was applied to the duct lumen, suggesting that SP and H2DIDS inhibit the same transporter on the apical membrane. As SLC26A6 is DIDS-sensitive, this isoform is the likely target for SP. The inhibitory effect of SP was mimicked by phorbol 12,13-dibutyrate (PDBu), an activator of protein kinase C (PKC). Moreover, bisindolylmaleimide, a blocker of PKC, relieved the inhibitory effect of both SP and PDBu on HCO3- secretion. Western blot analysis revealed that guinea pig pancreatic ducts express the α, β1, δ, ε, η, θ, ζ and μ isoforms of PKC. We conclude that PKC is negative regulator of SLC26 activity in pancreatic duct cells.

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KW - SLC26A6 as DIDS-sensitive

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