RAPID COMMUNICATIONcAMP regulates expression of the cyclic nucleotide transporter MRP4 (ABCC4) through the EPAC pathwayBröderdorf, Susanne; Zang, Sebastian; Schaletzki, Yvonne; Grube, Markus; Kroemer, Heyo K.; Jedlitschky, GabrieleAuthor Information Department of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine, Greifswald, Germany Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (www.pharmacogeneticsandgenomics.com). Present address: Heyo K. Kroemer: University Medicine Göttingen, Germany. Correspondence to Gabriele Jedlitschky, PhD, Department of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine, Felix-Hausdorff Street 3, D-17487 Greifswald, Germany Tel: +49 3834 8622146; fax: +49 3834 865631; e-mail: [email protected] Received December 18, 2013 Accepted July 18, 2014 Pharmacogenetics and Genomics: October 2014 - Volume 24 - Issue 10 - p 522-526 doi: 10.1097/FPC.0000000000000084 Buy SDC Metrics AbstractIn Brief Multidrug resistance protein 4 (MRP4/ABCC4) has been established as an independent regulator of cyclic AMP (cAMP) levels particularly in vascular smooth muscle cells and in hematopoietic cells. Here, we assessed whether cAMP in turn regulates MRP4. A significant upregulation of MRP4 mRNA and protein by long-term treatment with cAMP-enhancing agents was observed in HeLa cells, smooth muscle cells, and megakaryoblastic leukemia M07e cells. This upregulation was not affected by inhibition of protein kinase A, but could be reverted by inhibitors and siRNA of an alternative cAMP-signaling route involving exchange proteins activated by cyclic AMP (EPAC) and mitogen-activated protein kinases. A selective EPAC activator could equally induce MRP4. The transcriptional regulation was confirmed in a luciferase reporter gene assay using a vector containing a 1494-bp fragment of the promoter region of the MRP4/ABCC4 gene. Our results suggest that enhanced cAMP levels upregulate MRP4 expression, which can result in increased cAMP efflux. Supplemental Digital Content is available in the text. Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.