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J. Biol. Chem., Vol. 282, Issue 31, 22582-22591, August 3, 2007

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TRPV6 Is a Ca²⁺ Entry Channel Essential for Ca²⁺-induced Differentiation of Human Keratinocytes^*

V'yacheslav Lehen'kyi¹, Benjamin Beck², Renata Polakowska, Maria Charveron^¶, Pascal Bordat^¶, Roman Skryma³, and Natalia Prevarskaya³⁴

From the Inserm, U-800, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Université des Sciences et Technologies de Lille, F-59655 Villeneuve d'Ascq, France, Centre de Recherche Jean-Pierre Aubert, INSERM U-837, Faculty of Medicine, Universitédu Droit et de la Santé, 59045 Lille, France, and ^¶The Dermocosmetic Research Centre of "Pierre Fabre", 31322 Castanet-Tolosan, France

Ca²⁺ is an essential factor inducing keratinocyte differentiation due to the natural Ca²⁺ gradient in the skin. However, the membrane mechanisms that mediate calcium entry and trigger keratinocyte differentiation had not previously been elucidated. In this study we demonstrate that Ca²⁺-induced differentiation up-regulates both mRNA and protein expression of a transient receptor potential highly Ca²⁺-selective channel, TRPV6. The latter mediates Ca²⁺ uptake and accounts for the basal [Ca²⁺]_i in human keratinocytes. Our results show that TRPV6 is a prerequisite for keratinocyte entry into differentiation, because the silencing of TRPV6 in human primary keratinocytes led to the development of impaired differentiated phenotype triggered by Ca²⁺. The expression of such differentiation markers as involucrin, transglutaminase-1, and cytokeratin-10 was significantly inhibited by small interfering RNA-TRPV6 as compared with differentiated control cells. TRPV6 silencing affected cell morphology and the development of intercellular contacts, as well as the ability of cells to stratify. 1,25-Dihydroxyvitamin D3, a cofactor of differentiation, dose-dependently increased TRPV6 mRNA and protein expression in human keratinocytes. This TRPV6 up-regulation led to a significant increase in Ca²⁺ uptake in both undifferentiated and differentiated keratinocytes. We conclude that TRPV6 mediates, at least in part, the pro-differentiating effects of 1,25-dihydroxyvitamin D3 by increasing Ca²⁺ entry, thereby promoting differentiation. Taken together, these data suggest that the TRPV6 channel is a key element in Ca²⁺/1,25-dihydroxyvitamin D3-induced differentiation of human keratinocytes.

Received for publication, December 12, 2006 , and in revised form, June 4, 2007.

^* This work was supported in part by grants from Institut National de la Santé et de la Recherche Médicale, Ministère de l'Education Nationale, and the "Pierre Fabre" pharmaceutical company. 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 Supported by the Ministère de l'Education Nationale and Region Nord Pas-de Calais.

² Supported by the "Fondation pour la Recherche Médicale," France.

³ Shared senior authorship.

⁴ To whom correspondence should be addressed: Laboratory of Cell Physiology, INSERM U-800, University of Science and Technologies of Lille, 59650 Villeneuve d'Ascq, France. Tel.: 33-3-20-43-40-77; Fax: 33-3-20-43-40-66; E-mail: natacha.prevarskaya{at}univ-lille1.fr.

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