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First published on January 23, 2007; DOI: 10.1124/mol.106.030841

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Received for publication September 13, 2006.
Revised January 18, 2007.
Accepted for publication January 22, 2007.

Activation of Cyclic AMP (cAMP)-Dependent Signaling Pathway Induces Mouse Organic Anion Transporting Polypeptide 2 (Oatp2) Expression

Chuan Chen 1, Xingguo Cheng 1, Matthew Z Dieter 1, Yuji Tanaka 1, Curtis D Klaassen 1*

1 University of Kansas Medical Center

* Address correspondence to: E-mail: cklaasse{at}kumc.edu

Abstract

Rodent Oatp2 is a hepatic uptake transporter for compounds such as cardiac glycosides. In the present study, we found that fasting resulted in a two-fold induction of Oatp2 expression in liver of mice. Because cAMP-PKA signaling pathway is activated during fasting, the role of this pathway in Oatp2 induction during fasting was examined. In Hepa-1c1c7 cells, adenylyl cyclase activator forskolin as well as two cellular membrane-permeable cAMP analogs, dibutyryl cAMP and 8-bromo cAMP, induced Oatp2 mRNA expression in a time- and dose-dependent manner. These three chemicals induced reporter gene activity in cells transfected with a luciferase reporter gene construct containing a 7.6-kb 5'-flanking region of mouse Oatp2. Transient transfection of cells with 5'-deletion constructs derived from the 7.6-kb Oatp2 promoter reporter gene construct, as well as 7.6-kb constructs in which a consensus CRE half site CGTCA (-1808/-1804 bp) was mutated or deleted, confirms that this CRE site was required for the induction of luciferase activity by forskolin. Luciferase activity driven by the Oatp2 promoter containing this CRE site was induced in cells co-transfected with a plasmid encoding the protein kinase A catalytic subunit. Co-transfection of cells with a plasmid encoding the dominant-negative CRE binding protein (CREB) completely abolished the inducibility of the reporter gene activity by forskolin. In conclusion, induction of Oatp2 expression in liver of fasted mice may be caused by activation of the cAMP-dependent signaling pathway, with the CRE site (-1808/-1804) and CREB being the cis- and trans-acting factors mediating the induction, respectively.


Key words: cAMP, Protein Kinase A, CREB, Organic anion, Liver transporters


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