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J. Biol. Chem., Vol. 279, Issue 42, 43487-43496, October 15, 2004

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Characterization of C3a and C5a Receptors in Rat Cerebellar Granule Neurons during Maturation

NEUROPROTECTIVE EFFECT OF C5a AGAINST APOPTOTIC CELL DEATH^*

Magalie Bénard¶||, Bruno J. Gonzalez**, Marie-Thérèse Schouft¶, Anthony Falluel-Morel**, David Vaudry**, Philippe Chan¶, Hubert Vaudry**, and Marc Fontaine¶

From the European Institute for Peptide Research (IFRMP 23), ^¶INSERM U519, University of Rouen, 76183 Rouen, France, and ^**INSERM U413, University of Rouen, 76821 Mont-Saint-Aignan, France

There is now clear evidence that the Complement anaphylatoxin C3a and C5a receptors (C3aR and C5aR) are expressed in glial cells, notably in astrocytes and microglia. In contrast, very few data are available concerning the possible expression of these receptors in neurons. Here, we show that transient expression of C3aR and C5aR occurs in cerebellar granule neurons in vivo with a maximal density in 12-day-old rat, suggesting a role of these receptors during development of the cerebellum. Expression of C3aR and C5aR mRNAs and proteins was also observed in vitro in cultured cerebellar granule cells. Quantification of the mRNAs by real-time reverse transcription-PCR showed a peak of expression at day 2 in vitro (DIV 2); the C3aR and C5aR proteins were detected by Western blot analysis at DIV 4 and by flow cytometry and immunocytochemistry in differentiating neurons with a maximum density at DIV 4–9. Apoptosis of granule cells plays a crucial role for the harmonious development of the cerebellar cortex. We found that, in cultured granule neurons in which apoptosis was induced by serum deprivation and low potassium concentration, a C5aR agonist promoted cell survival and inhibited caspase-3 activation and DNA fragmentation. The neuroprotective effect of the C5aR agonist was associated with a marked inhibition of caspase-9 activity and partial restoration of mitochondrial integrity. Our results provide the first evidence that C3aR and C5aR are both expressed in cerebellar granule cells during development and that C5a, but not C3a, is a potent inhibitor of apoptotic cell death in cultured granule neurons.

Received for publication, April 14, 2004 , and in revised form, June 29, 2004.

^* 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.

Recipients of fellowships from the Lille-Amiens-Rouen-Caen-Neurosciences network and the Conseil Régional de Haute-Normandie.

^|| To whom correspondence should be addressed: INSERM U519, IFRMP 23, 22 boulevard Gambetta, 76183 Rouen Cedex France. Tel.: 33-235-14-8542; Fax: 33-235-14-8541; E-mail: magalie.benard{at}univrouen.fr.

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