%0 Journal Article %T Mechanism of inhibition of taurolithocholate©\induced retrieval of plasma membrane MRP2 by cyclic AMP and tauroursodeoxycholate %A Cynthia R. L. Webster %A Mohammed S. Anwer %A Se Won Park %J Archive of "Physiological Reports". %D 2017 %R 10.14814/phy2.13529 %X Taurolithocholate (TLC) produces cholestasis by inhibiting biliary solute secretion in part by retrieving MRP2 from the plasma membrane (PM). Tauroursodeoxycholate (TUDC) and cAMP reverse TLC©\induced cholestasis by inhibiting TLC©\induced retrieval of MRP2. However, cellular mechanisms for this reversal are incompletely understood. Recently, we reported that TLC decreases PM©\MRP2 by activating PKCŠĆ followed by phosphorylation of myristoylated alanine©\rich C kinase substrate (MARCKS). Thus, cAMP and TUDC may reverse TLC©\induced cholestasis by inhibiting the TLC/PKC ŠĆ/MARCKS phosphorylation pathway. We tested this hypothesis by determining whether TUDC and/or cAMP inhibit TLC©\induced activation of PKCŠĆ and phosphorylation of MARCKS. Studies were conducted in HuH©\NTCP cell line and rat hepatocytes. Activation of PKC ŠĆ was determined from the translocation of PKC ŠĆ to PM using a biotinylation method. Phosphorylation of MARCKS was determined by immunoblotting with a phospho©\MARCKS antibody. TLC, but not cAMP and TUDC, activated PKC ŠĆ and increased MARCKS phosphorylation in HuH©\NTCP as well in rat hepatocytes. Treatment with TUDC or cAMP inhibited TLC©\induced activation of PKCŠĆ and increases in MARCKS phosphorylation in both cell types. Based on these results, we conclude that the reversal of TLC©\induced cholestasis by cAMP and TUDC involves, at least in part, inhibition of TLC©\mediated activation of the PKCŠĆ/MARCKS phosphorylation pathway %K Cholestasis %K HuH©\NTCP cells %K MARCKS phosphorylation %K PKCŠĆ %K rat hepatocytes %U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727282/