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Protein kinase C mediates the inhibitory effect of substance P on HCO 3- secretion from guinea pig pancreatic ducts

Lookup NU author(s): Dr Zoltan Rakonczay, Dr Michael Gray, Professor Barry Argent

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Abstract

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 HCO 3- 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 α-, βI-, δ-, ε-, η-, θ-, ζ-, 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. Copyright © 2005 the American Physiological Society.


Publication metadata

Author(s): Hegyi P, Rakonczay Jr Z, Tiszlavicz L, Varro A, Toth A, Racz G, Varga G, Gray MA, Argent BE

Publication type: Article

Publication status: Published

Journal: American Journal of Physiology: Cell Physiology

Year: 2005

Volume: 288

Issue: 5

Pages: C1030-C1041

ISSN (print): 0363-6143

ISSN (electronic): 1522-1563

Publisher: American Physiological Society

URL: http://dx.doi.org/10.1152/ajpcell.00430.2003

DOI: 10.1152/ajpcell.00430.2003

PubMed id: 15625303


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