1. ^*Department of Dermatology, University of California, San Francisco, California, USA
2. ^†Dermatology Service, VA Medical Center, San Francisco, California, USA
3. ^‡Department of Dermatology, San Francisco General Hospital, San Francisco, California, USA
4. ^¶Department of Biomedical Sciences and Consiglio Nazionale delle Ricerche (CNR) Center for the Study of Biomembranes, University of Padova, Padova, Italy
5. ^§Department of Dermatology, Juntendo University School of Medicine, Tokyo, Japan
6. ^§§Center for Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory, Livermore, California, USA

Correspondence: Martin Behne MD, Dermatology Service (190), Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121. Email: behnemj@itsa.ucsf.edu

Received 12 December 2002; Revised 29 January 2003; Accepted 5 March 2003; Published online 25 September 2003.

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 Ca²⁺ ATPase ATP2C1, which controls Ca²⁺ concentrations in the cytoplasm and Golgi of human keratinocytes. Because actin reorganization is among the first responses to raised cytoplasmic Ca²⁺, we examined Ca²⁺-induced actin reorganization in normal and HHD keratinocytes. Even though HHD keratinocytes display raised baseline cytoplasmic Ca²⁺, we found that actin reorganization in response to Ca²⁺ 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 intra-cellular ATP concentration had been lowered pharmacologically. ATP concentrations in undifferentiated keratinocytes markedly declined after extracellular Ca²⁺ 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 Ca²⁺. This report provides new insights into how the ATP2C1-controlled ATP metabolism mediates Ca²⁺-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.