| Role of protein phosphatases in cyclic AMP-mediated stimulation of hepatic Na+/taurocholate cotransport. | |
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MedLine Citation:
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PMID: 9792726 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Cyclic AMP has been proposed to stimulate Na+/taurocholate (TC) cotransport in hepatocytes by translocating Na+/TC cotransport polypeptide (Ntcp) to the plasma membrane and to induce Ntcp dephosphorylation. Whether protein phosphatases 1 and 2A (PP1/2A) are involved in the regulation of Na+/TC cotransport by cAMP was investigated in the present study. Okadaic acid and tautomycin, inhibitors of PP1/2A, inhibited cAMP-mediated increases in TC uptake and cytosolic [Ca2+], and only tautomycin inhibited basal TC uptake. Removal of cAMP reversed cAMP-mediated increases in TC uptake and plasma membrane Ntcp mass. Okadaic acid alone increased Ntcp phosphorylation without affecting Ntcp mass in plasma membranes and homogenates. In the presence of okadaic acid, cAMP failed to increase plasma membrane Ntcp mass, induce Ntcp dephosphorylation, and decrease endosomal Ntcp mass. Phosphorylated Ntcp was detectable in endosomes isolated from okadaic acid-treated hepatocytes but not in endosomes from control and cAMP-treated hepatocytes. PP1 was found to be enriched in plasma membranes, whereas PP2A was mostly in the cytosol. Cyclic AMP did not activate either PP1 or PP2A, whereas okadaic acid inhibited primarily PP2A. These results suggest that 1) the effect of cAMP on Na+/TC cotransport is not mediated via either PP1 or PP2A; rather, cAMP-mediated signaling pathway is maintained by PP2A and inhibition of PP2A overrides cAMP-mediated effects, and 2) okadaic acid, by inhibiting PP2A, inhibits cAMP-mediated increases in Na+/TC cotransport by decreasing the ability of cAMP to increase cytosolic [Ca2+]. It is proposed that cAMP-mediated dephosphorylation of Ntcp leads to an increased retention of Ntcp in the plasma membrane, and okadaic acid, by inhibiting PP2A, inhibits cAMP-mediated stimulation of Na+/TC cotransport by reversing the ability of cAMP to increase cytosolic [Ca2+] and to induce Ntcp dephosphorylation. |
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Authors:
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S Mukhopadhyay; C R Webster; M S Anwer |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 273 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 1998 Nov |
Date Detail:
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Created Date: 1998-12-10 Completed Date: 1998-12-10 Revised Date: 2010-12-03 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 30039-45 Citation Subset: IM |
Affiliation:
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Department of Biomedical Sciences, Tufts University School of Veterinary Medicine, North Grafton, Massachusetts 01536, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antifungal Agents / pharmacology Biological Transport Calcium / metabolism Carrier Proteins / drug effects*, metabolism Cells, Cultured Cyclic AMP / pharmacology* Cytosol / drug effects, metabolism Enzyme Inhibitors / pharmacology Liver / drug effects*, metabolism Okadaic Acid / pharmacology Organic Anion Transporters, Sodium-Dependent* Phosphoprotein Phosphatases / antagonists & inhibitors, metabolism* Phosphorylation Pyrans* Rats Spiro Compounds* Symporters* |
| Grant Support | |
ID/Acronym/Agency:
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DK-33436/DK/NIDDK NIH HHS; K08 DK002721-01/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antifungal Agents; 0/Carrier Proteins; 0/Enzyme Inhibitors; 0/Organic Anion Transporters, Sodium-Dependent; 0/Pyrans; 0/Spiro Compounds; 0/Symporters; 109946-35-2/tautomycin; 145420-23-1/sodium-bile acid cotransporter; 60-92-4/Cyclic AMP; 7440-70-2/Calcium; 78111-17-8/Okadaic Acid; EC 3.1.3.16/Phosphoprotein Phosphatases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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