Activity of the hSPCA1 Golgi Ca2+ pump is essential for Ca2+-mediated Ca2+ response and cell viability in Darier disease
Activity of the hSPCA1 Golgi Ca2+ pump is essential for Ca2+-mediated Ca2+ response and cell viability in Darier disease
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DOI：
10.1242/jcs.02781
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发表时间：
2006-02-15
影响因子：
4
通讯作者：
Mauro, TM
中科院分区：
文献类型：
--
作者：
Foggia, L;Aronchik, I;Mauro, TM
角质形成细胞的分化、粘附和运动受细胞外Ca 2+浓度增加的影响，细胞外Ca 2+浓度增加又会增加细胞内Ca 2+水平。与大多数非兴奋细胞相反，正常角质形成细胞需要从高尔基体和内质网Ca 2+储存释放Ca 2+以进行有效的Ca 2+信号传导。由ATP 2C 1编码的高尔基体人类分泌途径Ca 2 +-ATP酶hSPCA 1的功能障碍，废除Ca 2+信号传导并引起棘层松解性遗传性皮肤病，Hailey-Hailey病。我们已经研究了内质网钙库的作用，建立和维持肌质和内质网钙ATP酶SERCA 2由ATP 2A 2编码，在钙信号。虽然以前的研究表明，急性SERCA 2失活废除Ca 2+信号，我们发现，慢性失活的ATP 2A 2在角质形成细胞从类似的棘层松解性遗传性皮肤病，Darier病的患者，不损害细胞外钙离子水平升高的反应。这种正常反应是由于hSPCA 1的补偿性上调，因为用siRNA灭活ATP 2C 1表达阻断了正常和Darier角质形成细胞中对升高的细胞外Ca 2+浓度的反应。ATP 2C 1失活也降低了Darier病角质形成细胞的活力，表明补偿性ATP 2C 1上调维持了活力，并部分补偿了Darier病角质形成细胞中内质网Ca 2 +-ATP酶的缺陷。因此，角质形成细胞在哺乳动物细胞中是独特的，它们能够使用高尔基体Ca 2+库来介导Ca 2+信号传导。
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.