Activity of the hSPCA1 Golgi Ca2+ pump is essential for Ca2+-mediated Ca2+ response and cell viability in Darier disease.
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.
INSERM U563, Purpan Hospital, Place du Dr Baylac, BP 2028, 31034 Toulouse CEDEX 3 and Université Paul Sabatier, 31062 Toulouse, France.
Lucie
L
Foggia
Ida
I
Aronchik
Karin
K
Aberg
Barbara
B
Brown
Alain
A
Hovnanian
Theodora M
TM
Mauro
D000818:Animals; D020013:Calcium Signaling / Q000235:genetics; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D007644:Darier Disease / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D015854:Up-Regulation
D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; C403624:ATP2C1 protein, human; D000252:Calcium-Transporting ATPases