Behne Martin J, Tu Chia-Ling, Aronchik Ida, Epstein Ervin, Bench Graham, Bikle Daniel D, Pozzan Tullio, Mauro Theodora M
Department of Dermatology, University of California, San Francisco, California, USA.
J Invest Dermatol. 2003 Oct;121(4):688-94. doi: 10.1046/j.1523-1747.2003.12528.x.
Hailey-Hailey disease (MIM16960) is a blistering skin disease caused by mutations in the Ca2+ ATPase ATP2C1. We found that the abnormal Ca2+ signaling seen in Hailey-Hailey disease keratinocytes correlates with decreased protein levels of ATP2C1. Human ATP2C1 protein approximated 115 kDa in size. The ATP2C1 is localized to the Golgi apparatus in human keratinocytes, similar to its localization in yeast and Caenorhabditis elegans. To test whether the ATP2C1 controls Golgi Ca2+ stores, we measured intraorganelle Ca2+ concentrations using specifically targeted aequorins. Whereas normal keratinocytes display Golgi Ca2+ levels comparable to other epithelial cells, Hailey-Hailey disease keratinocyte Golgi Ca2+ refill is slower, and the maximum Ca2+ concentration reached is significantly lower. These findings were replicated in vivo, because clinically normal Hailey-Hailey disease epidermis contained lower Ca2+ stores and displayed an abnormal Ca2+ gradient. In this report we localize the ATP2C1, demonstrate its physiologic relevance in mammalian cells, and measure intraorganelle Golgi Ca2+ in keratinocytes.
黑利-黑利病（MIM16960）是一种由钙离子ATP酶ATP2C1突变引起的水疱性皮肤病。我们发现，在黑利-黑利病角质形成细胞中观察到的异常钙离子信号与ATP2C1蛋白水平降低相关。人ATP2C1蛋白大小约为115 kDa。ATP2C1定位于人角质形成细胞的高尔基体，类似于其在酵母和秀丽隐杆线虫中的定位。为了测试ATP2C1是否控制高尔基体钙离子储存，我们使用特异性靶向水母发光蛋白测量细胞器内钙离子浓度。正常角质形成细胞的高尔基体钙离子水平与其他上皮细胞相当，而黑利-黑利病角质形成细胞高尔基体钙离子再填充较慢，且达到的最大钙离子浓度显著较低。这些发现在体内得到了验证，因为临床上正常的黑利-黑利病表皮含有较低的钙离子储存，并显示出异常的钙离子梯度。在本报告中，我们定位了ATP2C1，证明了其在哺乳动物细胞中的生理相关性，并测量了角质形成细胞内高尔基体的钙离子含量。
