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

Schonhoff, Christopher M.; Gillin, Henry; Webster, Cynthia R. L.; Anwer, Muhammad

doi:10.1002/hep.22162

Cited by 35 publications

(55 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PMA, a known activator of conventional and novel PKCs, activates p38 MAPK in LNCaP prostrate cancer cells (40), and PKC␦ has been shown to activate p38 MAPK (16) via MKK3 (27) in cardiac myocytes. We have recently reported that cAMP activates PKC␦ in hepatocytes (37). These results raise the possibility that cAMP-induced p38 MAPK activation may be mediated via cAMP-induced activation of PKC␦.…”

Section: Discussionmentioning

confidence: 74%

“…A cell surface protein biotinylation method as previously described by us (37,45,46) was used to assess Mrp2 translocation in hepatocytes and HuH-7 cells. Briefly, following various treatments, cell surface proteins were biotinylated by exposing hepatocytes to sulfo-NHS-LC-biotin (0.5 mg/ml; Pierce) followed by preparation of cell lysate used to determine biotinylated and total Mrp2 mass using immunoblot analysis.…”

Section: Methodsmentioning

confidence: 99%

“…However, little is known about the signaling pathways involved in cAMP-mediated Mrp2 translocation. We have recently reported that cAMP-induced Mrp2 translocation may involve PI3K-dependent PKC␦ activation (37); however, another study reported that cAMP-induced translocation of bile salt export pump (Bsep), another ABC transporter located at the canalicular membrane of hepatocytes (38), and Mrp2 is independent of PI3K activity (24). Other studies raise the possibility that the effect of cAMP may also be mediated via PI3K-independent activation of the p38 MAPK signaling pathway (see below).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Cyclic AMP stimulates Mrp2 translocation by activating p38α MAPK in hepatic cells

Schonhoff¹,

Webster

Anwer³

2010

American Journal of Physiology-Gastrointestinal and Liver Physi

Self Cite

View full text Add to dashboard Cite

Schonhoff CM, Webster CRL, Anwer MS. Cyclic AMP stimulates Mrp2 translocation by activating p38␣ MAPK in hepatic cells. Am J Physiol Gastrointest Liver Physiol 298: G667-G674, 2010. First published March 4, 2010 doi:10.1152/ajpgi.00506.2009 induces translocation of multidrug resistant protein 2 (Mrp2) to the canalicular membrane and activates p38 MAPK in rat hepatocytes. In this study, we tested the hypothesis that cAMPinduced Mrp2 translocation may be mediated via p38 MAPK. Studies were conducted in rat hepatocytes and in a human hepatoma cell line, HuH-7. In rat hepatocytes, cAMP increased Mrp2 translocation and p38 MAPK activity. These effects of cAMP were inhibited by SB203580, an inhibitor of p38 MAPK. Wortmannin, a specific inhibitor of phosphoinositide-3-kinase (PI3K), did not inhibit cAMP induced activation of p38 MAPK, indicating PI3K-independent activation of p38 MAPK by cAMP. To further define the role of p38 MAPK, molecular approaches were used to up-or downregulate p38 MAPK activity in HuH-7 cells using constitutively active (CA) and dominant-negative (DN) MAPK kinase 3 and 6 (MKK3/6). MKK3/6 are upstream kinases responsible for the activation of p38 MAPK. Cells transfected with CAMKK6 showed increased p38 MAPK activity and MRP2 translocation compared with empty vector. cAMPinduced activation of p38 MAPK was inhibited in cells transfected with DNMKK3/6 and DNMKK3, but not with DNMKK6. DNMKK3/6 and DNMKK3 also inhibited cAMP-induced MRP2 translocation. cAMP selectively activated p38␣ MAPK in HuH-7 cells. Knockdown of p38␣ MAPK by short heterodimer RNA resulted in decreased level of p38 MAPK and failure of cAMP to stimulate MRP2 translocation. Taken together, these results suggest that cAMPinduced MRP2 translocation in hepatic cells is mediated via PI3K-independent and MKK3-mediated activation of p38␣ MAPK. p38 MAPK isoforms; rat hepatocytes; Huh-7 cells; MAPK kinase; phosphoinositide-3-kinase

show abstract

Section: Discussionmentioning

confidence: 74%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Cyclic AMP stimulates Mrp2 translocation by activating p38α MAPK in hepatic cells

Schonhoff¹,

Webster

Anwer³

2010

American Journal of Physiology-Gastrointestinal and Liver Physi

Self Cite

View full text Add to dashboard Cite

show abstract

“…9D-F), which is in line with an involvement of PKC-isoforms in bile secretion. 21,26,46,47 The identification of the responsible isoform needs further investigation.…”

Section: Discussionmentioning

confidence: 99%

Short-term feedback regulation of bile salt uptake by bile salts in rodent liver

et al. 2012

View full text Add to dashboard Cite

The sodium taurocholate cotransporting polypeptide (Ntcp) is the major bile salt uptake transporter at the sinusoidal membrane of hepatocytes. Short-term feedback regulation of Ntcp by primary bile salts has not yet been investigated in vivo. Subcellular localization of Ntcp was analyzed in Ntcp-transfected HepG2-cells by flow cytometry and in immunofluorescence images from tissue sections by a new automated image analysis method. Net bile salt uptake was investigated in perfused rat liver by a pulse chase technique. In Flag-Ntcp-EGFP (enhanced green fluorescent protein) expressing HepG2-cells, taurochenodeoxycholate (TCDC), but not taurocholate (TC), induced endocytosis of Ntcp. TCDC, but not TC, caused significant internalization of Ntcp in perfused rat livers, as shown by an increase in intracellular Ntcp immunoreactivity, whereas Bsep distribution remained unchanged. These results correlate with functional studies. Rat livers were continuously perfused with 100 mu mol/L of TC. 25 mu mol/L of TCDC, taurodeoxycholate (TDC), tauroursodeoxycholate (TUDC), or TC were added for 30 minutes, washed out, followed by a pulse of (3)[H]-TC. TCDC, but not TDC, TUDC, or TC significantly increased the amount of (3)[H]-TC in the effluent, indicating a reduced sinusoidal net TC uptake. This effect was sensitive to chelerythrine (protein kinase C inhibitor) and cypermethrin (protein phosphatase 2B inhibitor). Phosphoinositide 3-kinase (PI3K) inhibitors had an additive effect, whereas Erk1/2 (extracellular signal activated kinase 1/2), p38MAPK, protein phosphatase 1/2A (PP1/2A), and reactive oxygen species (ROS) were not involved. Conclusion: TCDC regulates bile salt transport at the sinusoidal membrane by protein kinase C-and protein phosphatase 2B-mediated retrieval of Ntcp from the plasma membrane. During increased portal bile salt load this mechanism may adjust bile salt uptake along the acinus and protect periportal hepatocytes from harmful bile salt concentrations

show abstract

“…In addition to this PP2B-mediated pathway, NTCP's microfi lament-dependent insertion and retrieval from the plasma membrane is regulated by PI3-kinase ( 68 ). This PI3-kinase stimulated translocation is thought to be mediated in part via protein kinase C delta, as well as other signaling pathways (112)(113)(114)(115).…”

Section: Regulation Of Bsep Expression and Activitymentioning

confidence: 99%

Bile acid transporters

Dawson

Lan

Rao

2009

Journal of Lipid Research

592

456

View full text Add to dashboard Cite

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

Cited by 35 publications

References 53 publications

Cyclic AMP stimulates Mrp2 translocation by activating p38α MAPK in hepatic cells

Cyclic AMP stimulates Mrp2 translocation by activating p38α MAPK in hepatic cells

Short-term feedback regulation of bile salt uptake by bile salts in rodent liver

Bile acid transporters

Contact Info

Product

Resources

About