GSBS Student Publications

Title

Protein kinase Cdelta mediates cyclic adenosine monophosphate-stimulated translocation of sodium taurocholate cotransporting polypeptide and multidrug resistant associated protein 2 in rat hepatocytes

UMMS Affiliation

Graduate School of Biomedical Sciences; Department of Biomedical Sciences

Date

2-15-2008

Document Type

Article

Medical Subject Headings

1-Phosphatidylinositol 3-Kinase; ATP-Binding Cassette Transporters; Acetamides; Acetophenones; Animals; Benzopyrans; Cyclic AMP; Hepatocytes; Male; Organic Anion Transporters, Sodium-Dependent; Phosphorylation; Protein Kinase C-delta; Pyrans; Rats; Rats, Wistar; Spiro Compounds; Symporters; Taurocholic Acid

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

Cyclic adenosine monophosphate (cAMP) stimulates translocation of Na(+)-taurocholate (TC) cotransporting polypeptide (Ntcp) and multidrug resistant associated protein 2 (Mrp2) to the plasma membrane. Because cAMP activates phosphoinositide-3-kinase (PI3K) and protein kinase C (PKC) activation is PI3K-dependent, the aim of the current study was to determine whether cAMP activates conventional and novel PKCs in hepatocytes and whether such activation plays a role in cAMP-stimulated Ntcp and Mrp2 translocation. The effect of cAMP on PKCs, TC uptake, and Ntcp and Mrp2 translocation was studied in isolated rat hepatocytes using a cell-permeable cAMP analog, CPT-cAMP. The activity of PKCs was assessed from membrane translocation of individual PKCs, and phospho-specific antibodies were used to determine PKCdelta phosphorylation. TC uptake was determined from time-dependent uptake of (14)C-TC, and a cell surface biotinylation method was used to determine Ntcp and Mrp2 translocation. CPT-cAMP stimulated nPKCdelta but not cPKCalpha or nPKCepsilon, and induced PI3K-dependent phosphorylation of nPKCdelta at Thr(505). Rottlerin, an inhibitor of nPKCdelta, inhibited cAMP-induced nPKCdelta translocation, TC uptake, and Ntcp and Mrp2 translocation. Bistratene A, an activator of nPKCdelta, stimulated nPKCdelta translocation, TC uptake, and Ntcp and Mrp2 translocation. The effects of cAMP and bistratene A on TC uptake and Ntcp and Mrp2 translocation were not additive. Conclusion: These results suggest that cAMP stimulates Ntcp and Mrp2 translocation, at least in part, by activating nPKCdelta via PI3K-dependent phosphorylation at Thr(505).

Rights and Permissions

Citation: Hepatology. 2008 Apr;47(4):1309-16. Link to article on publisher's site

DOI of Published Version

10.1002/hep.22162

Related Resources

Link to Article in PubMed

Journal Title

Hepatology (Baltimore, Md.)

PubMed ID

18273864