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J. Biol. Chem., Vol. 282, Issue 45, 32710-32718, November 9, 2007

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Temperature-dependent Modulation of Ca_V3 T-type Calcium Channels by Protein Kinases C and A in Mammalian Cells^*

Jean Chemin¹, Alexandre Mezghrani, Isabelle Bidaud², Sebastien Dupasquier³, Fabrice Marger⁴, Christian Barrère, Joël Nargeot, and Philippe Lory

From the Département de Physiologie and the Département d'Oncologie Moléculaire et Cellulaire, Institut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Universités de Montpellier 1 et 2, Institut Fédératif de Recherche 3, Montpellier 34094, France

Modulation of low voltage-activated Ca_V3 T-type calcium channels remains poorly characterized compared with high voltage-activated Ca_V1 and Ca_V2 calcium channels. Notably, it is yet unresolved whether Ca_V3 channels are modulated by protein kinases in mammalian cells. In this study, we demonstrate that protein kinase A (PKA) and PKC (but not PKG) activation induces a potent increase in Ca_V3.1, Ca_V3.2, and Ca_V3.3 currents in various mammalian cell lines. Notably, we show that protein kinase effects occur at physiological temperature (30–37 °C) but not at room temperature (22–27 °C). This temperature dependence could involve kinase translocation, which is impaired at room temperature. A similar temperature dependence was observed for PKC-mediated increase in high voltage-activated Ca_V2.3 currents. We also report that neither Ca_V3 surface expression nor T-current macroscopic properties are modified upon kinase activation. In addition, we provide evidence for the direct phosphorylation of Ca_V3.2 channels by PKA in in vitro assays. Overall, our results clearly establish the role of PKA and PKC in the modulation of Ca_V3 T-channels and further highlight the key role of the physiological temperature in the effects described.

Received for publication, March 30, 2007 , and in revised form, September 12, 2007.

^* This work was supported in part by CNRS; Agence Nationale de la Recherche Research Grant ANR-05-NEUR-031; and research grants from Agence de Recherche contre le Cancer-Institut contre le Cancer 2006, the Institut UPSA de la Douleur, and the Association Française contre les Myopathies. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

² Supported by the Ligue Francaise contre l'Épilepsie.

³ Supported by the Ligue Régionale contre le Cancer (Languedoc-Roussillon).

⁴ Supported by a grant from Pfizer France.

¹ To whom correspondence should be addressed: Dépt. de Physiologie, Inst. de Génomique Fonctionnelle, 141, Rue de la Cardonille, Montpellier 34094, France. Tel.: 33-499-619-939; Fax: 33-499-619-901; E-mail: jean.chemin{at}igf.cnrs.fr.

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