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J. Biol. Chem., Vol. 278, Issue 42, 40670-40678, October 17, 2003

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Evidence for an Intracellular ADP-ribosyl Cyclase/NAD⁺-glycohydrolase in Brain from CD38-deficient Mice^*

Claire Ceni , Hélène Muller-Steffner , Frances Lund ¶, Nathalie Pochon , Annie Schweitzer ||, Michel De Waard , Francis Schuber , Michel Villaz  and Marie-Jo Moutin  **

From the Laboratoire Canaux Ioniques et Signalisation, INSERM E-9931, Département de Réponse et Dynamique Cellulaires-Commissariat à l'Energie Atomique (DRDC-CEA), 17 avenue des Martyrs, 38054 Grenoble, France, the Laboratoire de Chimie Bioorganique, UMR 7514 CNRS, Université Louis Pasteur Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67400 Strasbourg-Illkirch, France, the ^¶Trudeau Institute, Saranac Lake, New York, 12983, and the ^||Laboratoire Cytosquelette, INSERM U-366, DRDC-CEA, 17 avenue des martyrs, 38051 Grenoble, France

Cyclic ADP-ribose, a metabolite of NAD⁺, is known to modulate intracellular calcium levels and signaling in various cell types, including neural cells. The enzymes responsible for producing cyclic ADP-ribose in the cytoplasm of mammalian cells remain unknown; however, two mammalian enzymes that are capable of producing cyclic ADP-ribose extracellularly have been identified, CD38 and CD157. The present study investigated whether an ADP-ribosyl cyclase/NAD⁺-glycohydrolase independent of CD38 is present in brain tissue. To address this question, NAD⁺ metabolizing activities were accurately examined in developing and adult Cd38^-/- mouse brain protein extracts and cells. Low ADP-ribosyl cyclase and NAD⁺-glycohydrolase activities (in the range of pmol of product formed/mg of protein/min) were detected in Cd38^-/- brain at all developmental stages studied. Both activities were found to be associated with cell membranes. The activities were significantly higher in Triton X-100-treated neural cells compared with intact cells, suggesting an intracellular location of the novel cyclase. The cyclase and glycohydrolase activities were optimal at pH 6.0 and were inhibited by zinc, properties which are distinct from those of CD157. Both activities were enhanced by guanosine 5'-O-(3-thiotriphosphate), a result suggesting that the novel enzyme may be regulated by a G protein-dependent mechanism. Altogether our results indicate the presence of an intracellular membrane-bound ADP-ribosyl cyclase/NAD⁺-glycohydrolase distinct from CD38 and from CD157 in mouse brain. This novel enzyme, which is more active in the developing brain than in the adult tissue, may play an important role in cyclic ADP-ribose-mediated calcium signaling during brain development as well as in adult tissue.

Received for publication, February 4, 2003 , and in revised form, July 4, 2003.

^* Part of this work was supported by National Institutes of Health Grant AI43929 and the Trudeau Institute. 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.

^** To whom correspondence should be addressed: Laboratoire Canaux Ioniques et Signalisation, INSERM EMI 9931, DRDC-CEA, 17 avenue des martyrs, 38051 Grenoble Cedex 9, France. Tel.: 33-4-38-78-55-93; Fax: 33-4-38-78-50-41; E-mail: moutin{at}dsvgre.cea.fr.

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