Abstract
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.
Highlights
Changes in extracellular Ca2+ concentrations, as are seen in normal unperturbed epidermis or after epidermal permeability perturbation, control epidermal functions such as differentiation, barrier repair, keratinocyte cell-to-cell adhesion and keratinocyte motility (Fang et al, 1998; Mao-Qiang et al., 1997; Vasioukhin et al, 2000)
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
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
Summary
Changes in extracellular Ca2+ concentrations, as are seen in normal unperturbed epidermis or after epidermal permeability perturbation, control epidermal functions such as differentiation, barrier repair, keratinocyte cell-to-cell adhesion and keratinocyte motility (Fang et al, 1998; Mao-Qiang et al., 1997; Vasioukhin et al, 2000). Increasing extracellular Ca2+ concentration in cultured keratinocytes mimics many of the changes in keratinocyte differentiation and cell-to-cell adhesion seen in vivo (Pillai et al, 1990; Stanley and Yuspa, 1983; Vasioukhin et al, 2000), through a well-defined pathway that uses a plasma-membranebound Ca2+ receptor (CaR) to signal intracellular Ca2+ release, and subsequent long-lasting Ca2+ influx (Fatherazi et al, 2003; Oda et al, 1998). Initial studies found that emptying the endoplasmic reticulum (ER) Ca2+ store by pharmacologically inhibiting the Ca2+-ATPase, SERCA2, responsible for sequestering Ca2+, impaired the cells’ response to raised extracellular Ca2+ (Li et al, 1995). These studies suggested that keratinocytes, like most other non-excitable cells, used only the ER Ca2+ store
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