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- Title
Action Reorganization Is Abnormal and Cellular ATP Is Decreased in Hailey-Hailey Keratinocytes.
- Authors
Aronchik, Ida; Behne, Martin J.; Leypoldt, Laura; Crumrine, Debbie; Epstein, Ervin; Ikeda, Shigaku; Mizoguchi, Masayuki; Bench, Graham; Pozzan, Tullio; Mauro, Theodora
- Abstract
Actin reorganization and the formation of adherens junctions are necessary for normal cell-to-cell adhesion in keratinocytes. Hailey-Hailey disease (HHD) is blistering skin disease, resulting from mutations in the Ca[sup 2+] ATPase ATP2C1, which controls Ca[sup 2+] concentrations in the cytoplasm and Golgi of human keratinocytes. Because actin reorganization is among the first responses to raised cytoplasmic Ca[sup 2+], we examined Ca[sup 2+]-induced actin reorganization in normal and HHD keratinocytes. Even though HHD keratinocytes display raised baseline cytoplasmic Ca[sup 2+], we found that actin reorganization in response to Ca[sup 2+] was impaired in HHD keratinocytes. Defects in actin reorganization were linked to a marked decrease in cellular ATP in HHD keratinocytes, which persists, in vivo, in HHD epidermis. Defective actin reorganization was reproduced in normal keratinocytes in which the intracellular ATP concentration had been lowered pharmacologically. ATP concentrations in undifferentiated keratinocytes markedly declined after extracellular Ca[sup 2+] was increased, but then recovered to a new baseline that was approximately 150% of the previous baseline. In contrast, ATP concentrations in HHD keratinocytes did not change in response to increased extracellular Ca[sup 2+]. This report provides new insights into how the ATP2C1-controlled ATP metabolism mediates Ca[sup 2+]-induced cell-to-cell adhesion in normal keratinocytes. In addition, these findings implicate inadequate ATP stores as an additional cause in the pathogenesis of HHD and suggest novel therapeutic options.
- Subjects
KERATINOCYTES; ACTIN; ADENOSINE triphosphate
- Publication
Journal of Investigative Dermatology, 2003, Vol 121, Issue 4, p681
- ISSN
0022-202X
- Publication type
Article
- DOI
10.1046/j.1523-1747.2003.12472.x