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Originally published In Press as doi:10.1074/jbc.M010536200 on March 27, 2001

J. Biol. Chem., Vol. 276, Issue 24, 21642-21648, June 15, 2001
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Paracrine Roles of NAD+ and Cyclic ADP-ribose in Increasing Intracellular Calcium and Enhancing Cell Proliferation of 3T3 Fibroblasts*

Luisa FrancoDagger §, Elena Zocchi, Cesare Usai||, Lucrezia Guida, Santina Bruzzone, Aurora Costa**, and Antonio De FloraDagger Dagger

From the Dagger  G. Gaslini Institute, Largo G. Gaslini 5, 16147 Genova, Italy,  Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy, || Institute of Cybernetics and Biophysics, CNR, Via De Marini 6, 16149 Genova, Italy and ** Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian 1, 20133 Milano, Italy

CD38 is a bifunctional ectoenzyme synthesizing from NAD+ (ADP-ribosyl cyclase) and degrading (hydrolase) cyclic ADP-ribose (cADPR), a powerful universal calcium mobilizer from intracellular stores. Recently, hexameric connexin 43 (Cx43) hemichannels have been shown to release cytosolic NAD+ from isolated murine fibroblasts (Bruzzone, S., Guida, L., Zocchi, E., Franco, L. and De Flora, A. (2001) FASEB J. 15, 10-12), making this dinucleotide available to the ectocellular active site of CD38. Here we investigated transwell co-cultures of CD38+ (transfected) and CD38- 3T3 cells in order to establish the role of extracellular NAD+ and cADPR on [Ca2+]i levels and on proliferation of the CD38- target cells. CD38+, but not CD38-, feeder cells induced a [Ca2+]i increase in the CD38- target cells which was comparable to that observed with extracellular cADPR alone and inhibitable by NAD+-glycohydrolase or by the cADPR antagonist 8-NH2-cADPR. Addition of recombinant ADP-ribosyl cyclase to the medium of CD38- feeders induced sustained [Ca2+]i increases in CD38- target cells. Co-culture on CD38+ feeders enhanced the proliferation of CD38- target cells over control values and significantly shortened the S phase of cell cycle. These results demonstrate a paracrine process based on Cx43-mediated release of NAD+, its CD38-catalyzed conversion to extracellular cADPR, and influx of this nucleotide into responsive cells to increase [Ca2+]i and stimulate cell proliferation.

* This work was supported in part by grants from Associazione Italiana per la Ricerca sul Cancro, MURST-PRIN 2000, MURST-CNR (5% Project on Biotechnology to A. D. F.), and from the University of Genova and CNR (Target Project on Biotechnology to E. Z.).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.

§ Recipient of a fellowship from Fondo Sociale Europeo-MURST.

Dagger Dagger To whom correspondence should be addressed: Department of Experimental Medicine, 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 © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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