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lüll TRPV6 is a Ca2+ entry channel essential for Ca2+-induced differentiation of human keratinocytes Lehen'kyi V; Beck B; Polakowska R; Charveron M; Bordat P; Skryma R; Prevarskaya NJ Biol Chem 2007[Aug]; 282 (31): 22582-91Ca(2+) is an essential factor inducing keratinocyte differentiation due to the natural Ca(2+) 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 Ca(2+)-induced differentiation up-regulates both mRNA and protein expression of a transient receptor potential highly Ca(2+)-selective channel, TRPV6. The latter mediates Ca(2+) uptake and accounts for the basal [Ca(2+)](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 Ca(2+). 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 Ca(2+) 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 Ca(2+) entry, thereby promoting differentiation. Taken together, these data suggest that the TRPV6 channel is a key element in Ca(2+)/1,25-dihydroxyvitamin D3-induced differentiation of human keratinocytes.|Calcitriol/metabolism[MESH]|Calcium Channels/*metabolism/physiology[MESH]|Calcium/*metabolism[MESH]|Cell Differentiation[MESH]|Cell Line[MESH]|Cells, Cultured[MESH]|Dose-Response Relationship, Drug[MESH]|Humans[MESH]|Keratinocytes/*cytology/metabolism[MESH]|Phenotype[MESH]|RNA, Messenger/metabolism[MESH]|RNA, Small Interfering/metabolism[MESH]|TRPV Cation Channels/metabolism/*physiology[MESH]|Time Factors[MESH] |