UCSF

Ca(2+) fluxes direct keratinocyte differentiation, cell-to-cell adhesion, migration, and epidermal barrier homeostasis. We previously showed that intracellular Ca(2+) stores constitute a major portion of the calcium gradient especially in the stratum granulosum. Loss of the calcium gradient triggers epidermal barrier homeostatic responses. In this report, using unfixed ex vivo epidermis and human epidermal equivalents we show that endoplasmic reticulum (ER) Ca(2+) is released in response to barrier perturbation, and that this release constitutes the major shift in epidermal Ca(2+) seen after barrier perturbation. We find that ER Ca(2+) release correlates with a transient increase in extracellular Ca(2+). Lastly, we show that ER calcium release resulting from barrier perturbation triggers transient desmosomal remodeling, seen as an increase in extracellular space and a loss of the desmosomal intercellular midline. Topical application of thapsigargin, which inhibits the ER Ca(2+) ATPase activity without compromising barrier integrity, also leads to desmosomal remodeling and loss of the midline structure. These experiments establish the ER Ca(2+) store as a master regulator of the Ca(2+) gradient response to epidermal barrier perturbation, and suggest that ER Ca(2+) homeostasis also modulates normal desmosomal reorganization, both at rest and after acute barrier perturbation.