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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Protein kinase C mediates the inhibitory effect of substance P on HCO₃^– secretion from guinea pig pancreatic ducts

¹First Department of Medicine, ³Department of Pathology, and ⁴Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary; ²Institute for Cell & Molecular Biosciences, University of Newcastle Medical School, Newcastle upon Tyne, United Kingdom; and ⁵Molecular Oral Biology Research Group, Department of Oral Biology, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary

Submitted 6 January 2003 ; accepted in final form 10 December 2004

The inhibitory control of pancreatic ductal HCO₃^– secretion may be physiologically important in terms of limiting the hydrostatic pressure developed within the ducts and in terms of switching off pancreatic secretion after a meal. Substance P (SP) inhibits secretin-stimulated HCO₃^– secretion by modulating a Cl^–-dependent HCO₃^– efflux step at the apical membrane of the duct cell (Hegyi P, Gray MA, and Argent BE. Am J Physiol Cell Physiol 285: C268–C276, 2003). In the present study, we have shown that SP is present in periductal nerves within the guinea pig pancreas, that PKC mediates the effect of SP, and that SP inhibits an anion exchanger on the luminal membrane of the duct cell. Secretin (10 nM) stimulated HCO₃^– secretion by sealed, nonperfused, ducts about threefold, and this effect was totally inhibited by SP (20 nM). Phorbol 12,13-dibutyrate (PDBu; 100 nM), an activator of PKC, reduced basal HCO₃^– secretion by 40% and totally blocked secretin-stimulated secretion. In addition, bisindolylmaleimide I (1 nM to 1 µM), an inhibitor of PKC, relieved the inhibitory effect of SP on secretin-stimulated HCO₃^– secretion and also reversed the inhibitory effect of PDBu. Western blot analysis revealed that guinea pig pancreatic ducts express the -, _I-, -, -, -, -, -, and µ-isoforms of PKC. In microperfused ducts, luminal H₂DIDS (0.5 mM) caused intracellular pH to alkalinize and, like SP, inhibited basal and secretin-stimulated HCO₃^– secretion. SP did not inhibit secretion further when H₂DIDS was present in the lumen, suggesting that SP and H₂DIDS both inhibit the activity of an anion exchanger on the luminal membrane of the duct cell.

pancreas; Cl^–/HCO₃^– exchanger; inhibition; epithelium

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