Foggia Lucie, Aronchik Ida, Aberg Karin, Brown Barbara, Hovnanian Alain, Mauro Theodora M
INSERM U563, Purpan Hospital, Place du Dr Baylac, BP 2028, 31034 Toulouse CEDEX 3 and Université Paul Sabatier, 31062 Toulouse, France.
J Cell Sci. 2006 Feb 15;119(Pt 4):671-9. doi: 10.1242/jcs.02781.
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.
角质形成细胞的分化、黏附和迁移受细胞外钙离子浓度升高的调控，而细胞外钙离子浓度升高又会反过来提高细胞内钙离子水平。与大多数非兴奋性细胞不同，正常角质形成细胞需要从高尔基体和内质网钙离子库释放钙离子，以实现有效的钙离子信号传导。由ATP2C1编码的高尔基体人分泌途径钙离子 - ATP酶hSPCA1功能失调会消除钙离子信号传导，并导致棘层松解性遗传性皮肤病——黑利 - 黑利病。我们研究了由ATP2A2编码的肌浆网和内质网钙离子 - ATP酶SERCA2建立和维持的内质网钙离子库在钙离子信号传导中的作用。尽管先前的研究表明，急性SERCA2失活会消除钙离子信号传导，但我们发现，在患有类似棘层松解性遗传性皮肤病——达里埃病的患者角质形成细胞中，ATP2A2的慢性失活并不会损害对细胞外钙离子水平升高的反应。这种正常反应是由于hSPCA1的代偿性上调，因为用小干扰RNA使ATP2C1表达失活会阻断正常和达里埃角质形成细胞对细胞外钙离子浓度升高的反应。ATP2C1失活也会降低达里埃病角质形成细胞的活力，这表明ATP2C1的代偿性上调维持了细胞活力，并部分补偿了达里埃病角质形成细胞内质网钙离子 - ATP酶的缺陷。因此，角质形成细胞在利用高尔基体钙离子库介导钙离子信号传导的能力方面，在哺乳动物细胞中是独特的。
