title: SLC26 transporters and the inhibitory control of pancreatic ductal bicarbonate secretion.
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; a 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 (0.5mM) 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 alpha, beta1, delta, epsilon, eta, theta, zeta and mu isoforms o f PKC. We conclude that PKC is a negative regulator of SLC26 activity in pancreatic duct cells.
authors.affiliation: First Department of Medicine, Institute for Cell and Molecular Biosciences, University of Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Péter
authors.initials: P
authors.lastname: Hegyi
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Rakonczay
authors.forename: László
authors.initials: L
authors.lastname: Tiszlavicz
authors.forename: András
authors.initials: A
authors.lastname: Varró
authors.forename: András
authors.initials: A
authors.lastname: Tóth
authors.forename: Gábor
authors.initials: G
authors.lastname: Rácz
authors.forename: Gábor
authors.initials: G
authors.lastname: Varga
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gray
authors.forename: Barry E
authors.initials: BE
authors.lastname: Argent
mesh_terms: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017920:Antiporters / Q000378:metabolism*; D001639:Bicarbonates / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006168:Guinea Pigs; D010183:Pancreatic Ducts / Q000187:drug effects / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D012633:Secretin / Q000378:metabolism; D013373:Substance P / Q000378:metabolism
chemical_list: D017920:Antiporters; D001639:Bicarbonates; D012633:Secretin; D013373:Substance P; C018564:dihydro-DIDS; D011493:Protein Kinase C; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid