Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 282, Issue 31, Pages -Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M611398200
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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.
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