Abstract
The calcium-sensing receptor (CaSR) drives essential calcium ion (Ca(2+)) and E-cadherin‒mediated processes in the epidermis, including differentiation, cell-to-cell adhesion, and epidermal barrier homeostasis in cells and in young adult mice. We now report that decreased CaSR expression leads to impaired Ca(2+) signal propagation in aged mouse (aged >22 months) epidermis and human (aged >79 years, donor age) keratinocytes. Baseline cytosolic Ca(2+) concentrations were higher, and capacitive Ca(2+) entry was lower in aged than in young keratinocytes. As in Casr-knockout mice ((Epid)CaSR(-/-)), decreased CaSR expression led to decreased E-cadherin and phospholipase C-γ expression and to a compensatory upregulation of STIM1. Pretreatment with the CaSR agonist N-(3-[2-chlorophenyl]propyl)-(R)-alpha-methyl-3-methoxybenzylamine normalized Ca(2+) propagation and E-cadherin organization after experimental wounding. These results suggest that age-related defects in CaSR expression dysregulate normal keratinocyte and epidermal Ca(2+) signaling, leading to impaired E-cadherin expression, organization, and function. These findings show an innovative mechanism whereby Ca(2+)- and E-cadherin‒dependent functions are impaired in aging epidermis and suggest a new therapeutic approach by restoring CaSR function.