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Originally published In Press as doi:10.1074/jbc.M207793200 on October 3, 2002

J. Biol. Chem., Vol. 277, Issue 49, 47097-47105, December 6, 2002
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Equilibrative and Concentrative Nucleoside Transporters Mediate Influx of Extracellular Cyclic ADP-Ribose into 3T3 Murine Fibroblasts*

Lucrezia GuidaDagger §, Santina BruzzoneDagger §, Laura Sturla, Luisa Franco, Elena ZocchiDagger §, and Antonio De FloraDagger §||

From the Dagger  Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV/1, 16232, the § Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV/3, 16132, and the  G. Gaslini Institute, Largo G. Gaslini 5, 16147 Genova, Italy

In mammals cyclic ADP-ribose (cADPR), a universal calcium mobilizer from intracellular stores, is generated from NAD+ at the outer cell surface by the multifunctional ectoenzyme CD38 and by related ADP-ribosyl cyclases. Recently, influx of extracellular cADPR has been observed in 3T3 murine fibroblasts, where it elicits Ca2+-mediated enhancement of proliferation. Here we addressed the nature and the properties of cADPR influx into CD38- 3T3 cells, which showed pleiotropic mechanisms of both equilibrative and concentrative transport. Based on selective inhibitors or experimental conditions (e.g. abrogation of Na+-dependent active symport processes and transient transfection experiments) and on reverse transcriptase-polymerase chain reaction analysis of transcripts in 3T3 fibroblasts and comparatively in HeLa cells, we identified cADPR-transporting activities with specific nucleoside transporters (NT), both equilibrative (ENT2) and concentrative (CNT2 and a nitrobenzylthioinosine (NBMPR)-inhibitable NT). A reciprocal inhibition relationship was observed between inosine and cADPR fluxes across these NT species. Concentrative (but not equilibrative) transport of nanomolar extracellular cADPR took place in CD38- 3T3 cells co-cultured for 48 h in transwells on feeders of CD38-transfected, cADPR-generating 3T3 fibroblasts. These results suggest possible, hitherto unrecognized, correlations between ectocellular metabolism of nucleotides/nucleosides and cADPR-mediated regulation of intracellular calcium homeostasis.

* This work was supported in part by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC), MIUR-PRIN 2000, MIUR-CNR (5% Project on Biotechnology (to A. D. F.)), CNR (Target Project on Biotechnology (to E. Z.)), MIUR-FIRB (RBAUO19A3C), MIUR-University of Genova (Center of Excellence for Biomedical Research), Interuniversity Consortium on Biotechnology (CIB), and from the CARIGE Foundation.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: DI.ME.S., Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy. Tel.: 39-010-3538155; Fax: 39-010-5221944; E-mail: toninodf@unige.it.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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