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首页> 外文期刊>American Journal of Physiology >Role of PP2B in cAMP-induced dephosphorylation and translocation of NTCP.
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Role of PP2B in cAMP-induced dephosphorylation and translocation of NTCP.

机译：PP2B在cAMP诱导的NTCP脱磷酸和易位中的作用。

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摘要

cAMP-mediated stimulation of hepatic bile acid uptake is associated with dephosphorylation and translocation of Na+-taurocholate (TC) cotransporting peptide (NTCP) to the plasma membrane. Although translocation of NTCP may be facilitated by dephosphorylation, the mechanism of dephosphorylation is unknown. The ability of cAMP to translocate and dephosphorylate NTCP is, in part, dependent on cAMP-mediated increases in cytosolic Ca2+ concentration ([Ca2+]), indicating that a Ca2+/calmodulin-dependent protein phosphatase (PP2B) may be involved. Thus we studied the role of PP2B using the inhibitor cypermethrin (CM). Freshly isolated hepatocytes were pretreated with 1-5 nM CM for 30 min followed by 15 min incubation with 10 microM 8-(4-chlorophenylthio)cAMP. CM (5 nM) and FK-506 (5 microM) inhibited cAMP-stimulated TC uptake by 80 and 75%, respectively, without affecting basal TC uptake. CM also reversed cAMP-mediated NTCP dephosphorylation and translocation to 80 and 15% of the basal level, respectively. cAMP stimulated PP2B activity by 60%, and this effect was completely inhibited by 5 nM CM. PP2B dephosphorylated NTCP immunoprecipitated from control but not from cAMP-treated hepatocytes. The effect of CM was not due to any changes in cAMP-mediated increases in cytosolic [Ca2+] or decreases in mitogen-activated protein kinase (extracellular regulated kinases 1 and 2) activity. Taken together, these results suggest that cAMP dephosphorylates NTCP by activating PP2B in hepatocytes, and PP2B-mediated dephosphorylation of NTCP may be involved in cAMP-mediated NTCP translocation to the plasma membrane.
机译：cAMP介导的肝胆酸摄取刺激与去磷酸化和Na +-牛磺胆酸盐（TC）共转运肽（NTCP）转运到质膜有关。尽管脱磷酸可促进NTCP的易位，但脱磷酸的机理尚不清楚。 cAMP转运和去磷酸化NTCP的能力部分取决于cAMP介导的胞质Ca2 +浓度（[Ca2 +]）的增加，表明可能涉及Ca2 + /钙调蛋白依赖性蛋白磷酸酶（PP2B）。因此，我们使用抑制剂氯氰菊酯（CM）研究了PP2B的作用。将新鲜分离的肝细胞用1-5 nM CM预处理30分钟，然后与10 microM 8-（4-氯苯硫基）cAMP孵育15分钟。 CM（5 nM）和FK-506（5 microM）分别抑制cAMP刺激的TC摄取80％和75％，而不会影响基础TC摄取。 CM还逆转了cAMP介导的NTCP去磷酸化和易位，分别达到基础水平的80％和15％。 cAMP将PP2B活性提高了60％，而5 nM CM完全抑制了这种作用。 PP2B使磷酸化的NTCP从对照中免疫沉淀，但未从cAMP处理的肝细胞中沉淀。 CM的作用不是由于cAMP介导的胞质[Ca2 +]增加或丝裂原激活的蛋白激酶（细胞外调节的激酶1和2）活性降低引起的。综上所述，这些结果表明，cAMP通过激活肝细胞中的PP2B使NTCP脱磷酸，而PP2B介导的NTCP脱磷酸可能参与cAMP介导的NTCP向质膜的转运。

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