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J. Biol. Chem., Vol. 282, Issue 29, 20999-21004, July 20, 2007

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Hyaluronan Export by the ABC Transporter MRP5 and Its Modulation by Intracellular cGMP^*

Tobias Schulz, Udo Schumacher, and Peter Prehm¹

From the Institute of Physiological Chemistry and Pathobiochemistry, Muenster University Hospital, D-48129 Muenster, Germany and Institute for Anatomy II: Experimental Morphology, University Medical Centre Hamburg-Eppendorf, D-20246 Hamburg, Germany

Hyaluronan must be exported from its site of synthesis, the inner side of plasma membrane, to the extracellular matrix. Here, we identified the multidrug-associated protein MRP5 as the principle hyaluronan exporter from fibroblasts. The expression of the MRP5 (ABC-C5) transporter was silenced in fibroblasts using RNA interference, and a dose-dependent inhibition of hyaluronan export was observed. Hyaluronan oligosaccharides introduced into the cytosol competed with the export of endogenously labeled hyaluronan and the MRP5 substrate fluorescein. Because cGMP is a physiological substrate of MRP5, the intracellular concentrations of cGMP were modulated by the drugs 3-isobutyl-1-methylxanthin, propentofyllin, L-NAME, zaprinast, and bromo-cGMP, and the effects on hyaluronan export were analyzed. Increasing the cGMP levels inhibited hyaluronan export and decreasing it afforded higher concentrations of zaprinast to inhibit the export. Thus, cGMP may be a physiological regulator of hyaluronan export at the level of the export MRP5.

Received for publication, January 31, 2007 , and in revised form, May 30, 2007.

^* This work was supported by the Deutsche Forschungsgemeinschaft (SFB 492). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Muenster University Hospital, Inst. of Physiological Chemistry and Pathobiochemistry, Waldeyerstr. 15, D-48149 Münster, Germany. Tel.: 49-2518355579; Fax: 49-2518355596; E-mail: prehm{at}uni-muenster.de.

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