SLC26 transporters and the inhibitory control of pancreatic ductal bicarbonate secretion.
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.
Hegyi
Péter
P
First Department of Medicine, Institute for Cell and Molecular Biosciences, University of Newcastle upon Tyne, NE2 4HH, UK.
Rakonczay
Zoltán
Z
Tiszlavicz
László
L
Varró
András
A
Tóth
András
A
Rácz
Gábor
G
Varga
Gábor
G
Gray
Michael A
MA
Argent
Barry E
BE
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
D017920:Antiporters; D001639:Bicarbonates; D012633:Secretin; D013373:Substance P; C018564:dihydro-DIDS; D011493:Protein Kinase C; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid