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J. Biol. Chem., Vol. 280, Issue 30, 28044-28052, July 29, 2005

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Secretory Phospholipases A₂ Induce Neurite Outgrowth in PC12 Cells through Lysophosphatidylcholine Generation and Activation of G2A Receptor^*

Yutaka Ikeno, Naoko Konno, So-hyun Cheon, Angelo Bolchi, Simone Ottonello, Katsuhiko Kitamoto, and Manabu Arioka¶

From the Department of Biotechnology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan and the Dipartimento di Biochimica e Biologia Molecolare, Università di Parma, Parco Area delle Scienze 23/A, I-43100 Parma, Italy

We previously demonstrated that secretory phospholipase A₂ (sPLA₂) and lysophosphatidylcholine (LPC) exhibit neurotrophin-like neuritogenic activity in the rat pheochromocytoma cell line PC12. In this study, we further analyzed the mechanism whereby sPLA₂ displays neurite-inducing activity. Exogenously added mammalian group X sPLA₂ (sPLA₂-X), but not group IB and IIA sPLA₂s, induced neuritogenesis, which correlated with the ability of sPLA₂-X to liberate LPC into the culture media. In accordance, blocking the effect of LPC by supplementation of bovine serum albumin or phospholipase B attenuated neuritogenesis by sPLA₂ or LPC. Overproduction or suppression of G2A, a G-protein-coupled receptor involved in LPC signaling, resulted in the enhancement or reduction of neuritogenesis induced by sPLA₂ treatment. These results indicate that the neuritogenic effect of sPLA₂ is mediated by generation of LPC and subsequent activation of G2A.

Received for publication, March 28, 2005 , and in revised form, May 25, 2005.

^* This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan, and by a grant from Amano Enzyme Inc. 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: Tel.: 81-3-5841-5163; Fax: 81-3-5841-8033; E-mail: arioka{at}mail.ecc.u-tokyo.ac.jp.

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