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First published online February 8, 2006
doi: 10.1242/10.1242/jcs.02781

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Activity of the hSPCA1 Golgi Ca²⁺ pump is essential for Ca²⁺-mediated Ca²⁺ response and cell viability in Darier disease

¹ INSERM U563, Purpan Hospital, Place du Dr Baylac, BP 2028, 31034 Toulouse CEDEX 3 and Université Paul Sabatier, 31062 Toulouse, France
² Department of Dermatology, University of California, 4150 Clement Street, San Francisco, CA 94131, USA
³ Department of Medical Genetics, Purpan Hospital, Place du Dr Baylac, 31059 Toulouse CEDEX 3, France
⁴ Dermatology Service, Department of Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94131, USA

^* Authors for correspondence (e-mail: tmauro{at}itsa.ucsf.edu;alain.hovnanian{at}toulouse.inserm.fr)

Accepted 1 November 2005

Keratinocyte differentiation, adhesion and motility are directed by extracellular Ca²⁺ concentration increases, which in turn increase intracellular Ca²⁺ levels. Normal keratinocytes, in contrast to most non-excitable cells, require Ca²⁺ release from both Golgi and endoplasmic reticulum Ca²⁺ stores for efficient Ca²⁺ signaling. Dysfunction of the Golgi human secretory pathway Ca²⁺-ATPase hSPCA1, encoded by ATP2C1, abrogates Ca²⁺ signaling and causes the acantholytic genodermatosis, Hailey-Hailey disease. We have examined the role of the endoplasmic reticulum Ca²⁺ store, established and maintained by the sarcoplasmic and endoplasmic reticulum Ca²⁺-ATPase SERCA2 encoded by ATP2A2, in Ca²⁺ signaling. Although previous studies have shown acute SERCA2 inactivation to abrogate Ca²⁺ signaling, we find that chronic inactivation of ATP2A2 in keratinocytes from patients with the similar acantholytic genodermatosis, Darier disease, does not impair the response to raised extracellular Ca²⁺ levels. This normal response is due to a compensatory upregulation of hSPCA1, as inactivating ATP2C1 expression with siRNA blocks the response to raised extracellular Ca²⁺ concentrations in both normal and Darier keratinocytes. ATP2C1 inactivation also diminishes Darier disease keratinocyte viability, suggesting that compensatory ATP2C1 upregulation maintains viability and partially compensates for defective endoplasmic reticulum Ca²⁺-ATPase in Darier disease keratinocytes. Keratinocytes thus are unique among mammalian cells in their ability to use the Golgi Ca²⁺ store to mediate Ca²⁺ signaling.

Key words: Darier, Hailey-Hailey, SERCA2, hSPCA1, Calcium, Keratinocytes

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