Origin of the epidermal calcium gradient: regulation by barrier status and role of active vs passive mechanisms.

Mammalian epidermis displays a characteristic calcium gradient, with low calcium levels in the lower, basal, and spinous epidermal layers, whereas calcium levels increase progressively towards the outer stratum granulosum, and declining again in the stratum corneum. As the calcium gradient disappears after acute permeability barrier disruption, and returns after 6 h in parallel with barrier recovery, barrier function (through restriction of transcutaneous water movement) could regulate the formation of the epidermal calcium gradient. Two types of experiments confirmed the role of barrier status in regulating the calcium gradient: (i) either a vapor-permeable membrane (Gore-Tex) or an emollient (Vaseline), applied after acute barrier disruption, immediately restored barrier function, while accelerating the return of the calcium gradient, and (ii) in contrast, applications of lovastatin, a cholesterol synthesis inhibitor, which delayed barrier recovery and retarded the return of the calcium gradient. We next asked whether the calcium gradient is formed/maintained by passive and/or active mechanisms. Previous studies have demonstrated that cold exposure (4 degrees C) blocks permeability barrier recovery after acute disruption. Here, we abrogated the barrier with tape-stripping, and then compared barrier recovery and restoration of the calcium gradient in hairless mice exposed to 4 degrees C external temperatures, with and without occlusion with Gore-Tex. Although low levels of returned calcium throughout the epidermis, acutely disrupted, unoccluded, cold-exposed sites showed neither barrier recovery nor reappearance of the calcium gradient at 5 h. In contrast, acutely disrupted, cold-exposed sites, covered with Gore-Tex, likewise displayed little barrier recovery, but the calcium gradient largely returned by 3 h. These results show that (i) barrier status regulates formation of the calcium gradient, and (ii) passive processes alone can account for the formation/maintenance of the calcium gradient.