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J. Biol. Chem., Vol. 283, Issue 7, 4133-4144, February 15, 2008

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Neuroprotection by Neurotrophic Factors and Membrane Depolarization Is Regulated by Calmodulin Kinase IV^*

M. José Pérez-García¹, Myriam Gou-Fabregas², Yolanda de Pablo³, Marta Llovera, Joan X. Comella⁴⁵, and Rosa M. Soler⁵⁶

From the Cell Signaling and Apoptosis Group, Departament de Ciències Mèdiques Bàsiques, Facultat de Medicina and Hospital Universitari Arnau de Vilanova, Laboratori de Recerca, Universitat de Lleida, Institut de Recerca Biomèdica de Lleida, Montserrat Roig, 2, 25008-Lleida, Spain

Neurotrophic factors promote motoneuron (MN) survival through increased intracellular calcium (Ca²⁺) and regulation of the phosphatidylinositol (PI) 3-kinase/protein kinase B (PKB) pathway by calmodulin (CaM). Activation of the PI 3-kinase/PKB pathway is one of the well established mechanisms involved in MN survival. The Ca²⁺/CaM complex interacts with and modulates the functionality of a large number of proteins, including serine/threonine protein kinases such as Ca²⁺/CaM-dependent protein kinases (CaMKs). Using a primary culture of embryonic chicken spinal cord MNs, we investigated the role of CaMKIV in mediating this process. We cloned chicken CaMKIV and demonstrated its expression in purified MNs by means of reverse transcription-PCR, Western blot, and immunofluorescence. Using RNA interference, we show that endogenous CaMKIV mediates cell survival induced by neurotrophic factors or membrane depolarization. The survival effect is independent of CaMKIV kinase activity; however, CaMKIV functionality depends on the presence of Ca²⁺/CaM. Finally, CaMKIV associates to the p85 subunit of PI 3-kinase in a Ca²⁺-dependent manner, suggesting a role in regulating PI 3-kinase/PKB activation.

Received for publication, July 5, 2007 , and in revised form, December 11, 2007.

^* This work was supported in part by Ministerio de Sanidad y Consumo Fondo de Investigaciones Sanitarias Grants PI051445 (to R. M. S.) and PI042537 (to M. Ll.) and by Suport a Grups de Recerca Consolidats from Generalitat de Catalunya (to J. X. 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.

¹ Holds a fellowship from Ministerio de Educación y Ciencia.

² Holds a fellowship from Universitat de Lleida.

³ Holds a fellowship from Ministerio de Educación y Ciencia.

⁴ Present address: Departament de Bioquímica i Biologia Molecular, Institut de Neurociencies, Universitat Autonoma de Barcelona, 08193-Cerdanyola del Valles, Spain.

⁵ Senior co-authors.

⁶ To whom correspondence should be addressed. Tel.: 34-973-70-24-07; Fax: 34-973-70-24-26; E-mail: rosa.soler{at}cmb.udl.es.

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