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J. Biol. Chem., Vol. 279, Issue 7, 6132-6142, February 13, 2004

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Glial Cell Line-derived Neurotrophic Factor Increases Intracellular Calcium Concentration

ROLE OF CALCIUM/CALMODULIN IN THE ACTIVATION OF THE PHOSPHATIDYLINOSITOL 3-KINASE PATHWAY^*

M. José Pérez-García, Valentín Ceña, Yolanda de Pablo, Marta Llovera, Joan X. Comella¶, and Rosa M. Soler¶||

From the Grup de Neurobiologia Molecular, Departament de Ciències Mèdiques Bàsiques, Facultat de Medicina, Universitat de Lleida, 44 Rovira Roure, 25198 Lleida and the Universidad de Castilla-La Mancha, Centro Regional de Investigaciones Biomédicas, Avda. Almansa, s/n, 02071 Albacete, Spain

Moderate increases of intracellular Ca²⁺ concentration ([Ca²⁺]_i), induced by either the activation of tropomyosin receptor kinase (Trk) receptors for neurotrophins or by neuronal activity, regulate different intracellular pathways and neuronal survival. In the present report we demonstrate that glial cell line-derived neurotrophic factor (GDNF) treatment also induces [Ca²⁺]_i elevation by mobilizing this cation from internal stores. The effects of [Ca²⁺]_i increase after membrane depolarization are mainly mediated by calmodulin (CaM). However, the way in which CaM exerts its effects after tyrosine kinase receptor activation remains poorly characterized. It has been reported that phosphatidylinositol 3-kinase (PI 3-kinase) and its downstream target protein kinase B (PKB) play a central role in cell survival induced by neurotrophic factors; in fact, GDNF promotes neuronal survival through the activation of the PI 3-kinase/PKB pathway. We show that CaM antagonists inhibit PI 3-kinase and PKB activation as well as motoneuron survival induced by GDNF. We also demonstrate that endogenous Ca²⁺/CaM associates with the 85-kDa regulatory subunit of PI 3-kinase (p85). We conclude that changes of [Ca²⁺]_i, induced by GDNF, promote neuronal survival through a mechanism that involves a direct regulation of PI 3-kinase activation by CaM thus suggesting a central role for Ca²⁺ and CaM in the signaling cascade for neuronal survival mediated by neurotrophic factors.

Received for publication, July 31, 2003 , and in revised form, November 19, 2003.

^* This work has been supported by Grant Fondo de Investigación Sanitaria (PI021357) from the Ministerio de Sanidad y Consumo (to R. M. S.); by Grant SAF2000-0164-C02-01 from the Ministerio de Ciencia y Tecnología and Grant QLG3-CT-1999-00602 from the European Commission, Suport a Grups de Recerca Consolidats, and Distinció Joves Investigadors from Generalitat de Catalunya (to J. X. C.); by Grant BFI2001-1565 from the Ministerio de Ciencia y Tecnología, Grant G03/167 from the Ministerio de Sanidad, and Grant PAI-02-031 from the Consejería de Ciencia y Tecnología, Junta de Comunidades Castilla-La Mancha, and the Fundación Campollano-Banco Santander Central Hispano (to V. C.). 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.

^¶ Senior co-authors.

^|| To whom correspondence should be addressed. Tel.: 34-973-70-24-14; Fax: 34-973-70-24-38; E-mail: rosa.soler{at}cmb.udl.es.

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