Reevaluation of the Normal Epidermal Calcium Gradient, and Analysis of Calcium Levels and ATP Receptors in Hailey–Hailey and Darier Epidermis

Abstract

Electron probe microanalysis was used to analyze elemental content of human epidermis. The results revealed that the calcium content of the basal keratinocyte layer was higher than that of the lowest spinous cell layer in normal epidermis. This was surprising, as it is generally accepted that the calcium level increases with cellular differentiation from the proliferative basal layer to the stratum corneum. Hailey-Hailey disease (HHD) and Darier disease (DD) are caused by mutations in Ca(2+)-ATPases with the end result of desmosomal disruption and suprabasal acantholysis. The results demonstrated three major aberrations in HHD and DD lesions. First, in HHD and DD lesions the calcium content in the basal layer was lower than in the normal skin. Second, adenosine triphosphate (ATP) receptor P2Y2 was not localized to plasma membrane in acantholytic cells, whereas P2X7 appeared in the plasma membrane, potentially mediating apoptosis. Third, transition of keratin 14 to keratin 10 was abnormal as demonstrated by the presence of keratinocytes expressing both cytokeratins, which are usually exclusive in normal epidermis. Our results provide to our knowledge previously unreported elements for understanding how the disturbed calcium gradient is linked to the alterations in ATP receptors and keratin expression, leading to the clinical findings in HHD and DD.

The epithelial sodium channel mediates the directionality of galvanotaxis in human keratinocytes

“…A 20-65 mV potential difference is measured between the surface of the epithelium and dermis (Barker et al, 1982;Foulds and Barker, 1983) with the inside positive relative to the surface. The non-conductive stratum corneum and polar distribution of higher concentrations of cations including calcium, potassium and sodium within the upper level of the epidermis (Denda et al, 2000;Leinonen et al, 2009) are hypothesized to maintain this transepithelial potential.…”

Familial benign chronic pemphigus (Hailey-Hailey Disease): use of topical immunomodulators as a modern treatment option

“…The distribution of intracellular Ca 2+ plays an important role in the regulation of cell-cell interactions in the epidermis 3 . damage of desmosomes gives rise to acantholysis, the characteristic finding in hailey-hailey disease.…”

“…it is hypothesized that the main reason for the pathologic changes is an altered protein composition of desmosomes leading to acantholysis, deriving from ATP 2 C 1 gene mutation localized on chromosome 3q 2 . The ATP 2 C 1 gene codes a Ca 2+ -pump that regulates the transportation of calcium from the cytosol into the Golgi apparatus 2,3 . in approximately 70% of the cases a positive family history may be elicited.…”

β-Adducin siRNA disruption of the spectrin-based cytoskeleton in differentiating keratinocytes prevented by calcium acting through calmodulin/epidermal growth factor receptor/cadherin pathway

“…This skeletal protein that functions as an F-actin capping protein is always observed in association with spectrin and actin in tissues and cultured cells [5,10]. Spectrins are ubiquitous scaffolding components of the membrane skeleton that organize and stabilize microdomains on both the plasma membrane and the intracellular organelles [11].…”