Role of the PI3K/PKB signaling pathway in cAMP-mediated translocation of rat liver Ntcp.
cAMP stimulates Na(+)-taurocholate (TC) cotransport by translocating the Na(+)-TC-cotransporting peptide (Ntcp) to the plasma membrane. The present study was undertaken to determine whether the phosphatidylinositol-3-kinase (PI3K)-signaling pathway is involved in cAMP-mediated translocation of Ntcp. The ability of cAMP to stimulate TC uptake declined significantly when hepatocytes were pretreated with PI3K inhibitors wortmannin or LY-294002. Wortmannin inhibited cAMP-mediated translocation of Ntcp to the plasma membrane. cAMP stimulated protein kinase B (PKB) activity by twofold within 5 min, an effect inhibited by wortmannin. Neither basal mitogen-activated protein kinase (MAPK) activity nor cAMP-mediated inhibition of MAPK activity was affected by wortmannin. cAMP also stimulated p70(S6K) activity. However, rapamycin, an inhibitor of p70(S6K), failed to inhibit cAMP-mediated stimulation of TC uptake, indicating that the effect of cAMP is not mediated via p70(S6K). Cytochalasin D, an inhibitor of actin filament formation, inhibited the ability of cAMP to stimulate TC uptake and Ntcp translocation. Together, these results suggest that the stimulation of TC uptake and Ntcp translocation by cAMP may be mediated via the PI3K/PKB signaling pathway and requires intact actin filaments.
Webster
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Departments of Biomedical Sciences and Clinical Sciences, Tufts University School of Veterinary Medicine, North Grafton, Massachusetts 01536, USA.
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D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000201:enzymology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology*; D015638:Cytochalasin D / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000201:enzymology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D026901:Membrane Transport Proteins; D009025:Morpholines / Q000494:pharmacology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D029363:Organic Anion Transporters, Sodium-Dependent; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D012964:Sodium / Q000493:pharmacokinetics; D027981:Symporters; D013656:Taurocholic Acid / Q000493:pharmacokinetics; D000077191:Wortmannin
D000730:Androstadienes; D000900:Anti-Bacterial Agents; D002118:Calcium; D002352:Carrier Proteins; D002867:Chromones; D000242:Cyclic AMP; D015638:Cytochalasin D; D004791:Enzyme Inhibitors; D026901:Membrane Transport Proteins; D009025:Morpholines; D019384:Nucleic Acid Synthesis Inhibitors; D029363:Organic Anion Transporters, Sodium-Dependent; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus; D012964:Sodium; D027981:Symporters; D013656:Taurocholic Acid; D000077191:Wortmannin; C071908:sodium-bile acid cotransporter; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one