| First Author | Schonhoff CM | Year | 2016 |
| Journal | Am J Physiol Gastrointest Liver Physiol | Volume | 310 |
| Issue | 11 | Pages | G999-G1005 |
| PubMed ID | 27012769 | Mgi Jnum | J:234863 |
| Mgi Id | MGI:5791022 | Doi | 10.1152/ajpgi.00005.2016 |
| Citation | Schonhoff CM, et al. (2016) p38 MAPK alpha and beta isoforms differentially regulate plasma membrane localization of MRP2. Am J Physiol Gastrointest Liver Physiol 310(11):G999-G1005 |
| abstractText | In hepatocytes, cAMP both activates p38 mitogen-activated protein kinase (MAPK) and increases the amount of multidrug resistance-associated protein-2 (MRP2) in the plasma membrane (PM-MRP2). Paradoxically, taurolithocholate (TLC) activates p38 MAPK but decreases PM-MRP2 in hepatocytes. These opposing effects of cAMP and TLC could be mediated via different p38 MAPK isoforms (alpha and beta) that are activated differentially by upstream kinases (MKK3, MKK4, and MKK6). Thus we tested the hypothesis that p38alpha MAPK and p38beta MAPK mediate increases and decreases in PM-MRP2 by cAMP and TLC, respectively. Studies were conducted in hepatocytes isolated from C57BL/6 wild-type (WT) and MKK3-knockout (MKK3(-/-)) mice and in a hepatoma cell line (HuH7) that overexpresses sodium-taurocholate cotransporting polypeptide (NTCP) (HuH-NTCP). Cyclic AMP activated MKK3, p38 MAPK, and p38alpha MAPK and increased PM-MRP2 in WT hepatocytes, but failed to activate p38alpha MAPK or increase PM-MRP2 in MKK3(-/-) hepatocytes. In contrast to cAMP, TLC activated total p38 MAPK but decreased PM-MRP2, and did not activate MKK3 or p38alpha MAPK in WT hepatocytes. In MKK3(-/-) hepatocytes, TLC still decreased PM-MRP2 and activated p38 MAPK, indicating that these effects are not MKK3-dependent. Additionally, TLC activated MKK6 in MKK3(-/-) hepatocytes, and small interfering RNA knockdown of p38beta MAPK abrogated TLC-mediated decreases in PM-MRP2 in HuH-NTCP cells. Taken together, these results suggest that p38alpha MAPK facilitates plasma membrane insertion of MRP2 by cAMP, whereas p38beta MAPK mediates retrieval of PM-MRP2 by TLC. |
