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J. Biol. Chem. 275 (39): 30069-30074

© 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

The Multidrug Resistance Protein 5 Functions as an ATP-dependent Export Pump for Cyclic Nucleotides*

Gabriele JedlitschkyDagger §, Brian Burchell, and Dietrich KepplerDagger

From the Dagger  Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, D-69120 Heidelberg, Germany and the  Department of Molecular and Cellular Pathology, University of Dundee, Dundee DD1 9SY, Scotland, United Kingdom

Cellular export of cyclic nucleotides has been observed in various tissues and may represent an elimination pathway for these signaling molecules, in addition to degradation by phosphodiesterases. In the present study we provide evidence that this export is mediated by the multidrug resistance protein isoform MRP5 (gene symbol ABCC5). The transport function of MRP5 was studied in V79 hamster lung fibroblasts transfected with a human MRP5 cDNA. An MRP5-specific antibody detected an overexpression of the glycoprotein of 185 ± 15 kDa in membranes from MRP5-transfected cells and a low basal expression of hamster Mrp5 in control membranes. ATP-dependent transport of 3',5'-cyclic GMP at a substrate concentration of 1 µM was 4-fold higher in membrane vesicles from MRP5-transfected cells than in control membranes. This transport was saturable with a Km value of 2.1 µM. MRP5-mediated transport was also detected for 3',5'-cyclic AMP at a lower affinity, with a Km value of 379 µM. A potent inhibition of MRP5-mediated transport was observed by several compounds, known as phosphodiesterase modulators, including trequinsin, with a Ki of 240 nM, and sildenafil, with a Ki value of 267 nM. Thus, cyclic nucleotides are physiological substrates for MRP5; moreover, MRP5 may represent a novel pharmacological target for the enhancement of tissue levels of cGMP.

* The work on the cloning of MRP5 was supported in part by a research grant from the Deutsche Forschungsgemeinschaft (to G. J.) and a grant from the Wellcome Trust (to B. B.). The stable expression, transport, and inhibitor studies were supported by the Deutsches Krebsforschungszentrum and grants from the Deutsche Forschungsgemeinschaft through Sonderforschungsbereich 601 and 352, Heidelberg, Germany.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. Tel.: 49-6221-422405; Fax: 49-6221-422402; E-mail: g.jedlitschky@dkfz-heidelberg.de.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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