Decreased Calcium-Sensing Receptor Expression Controls Calcium Signaling and Cell-To-Cell Adhesion Defects in Aged Skin

The calcium-sensing receptor (CaSR) drives essential calcium ion (Ca2+) 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 Ca2+ signal propagation in aged mouse (aged >22 months) epidermis and human (aged >79 years, donor age) keratinocytes. Baseline cytosolic Ca2+ concentrations were higher, and capacitive Ca2+ entry was lower in aged than in young keratinocytes. As in Casr-knockout mice ((CaSR-/-)-Ca-Epid), decreased CaSR expression led to decreased E-cadherin and phospholipase C-gamma expression and to a compensatory upregulation of STIM1. Pretreatment with the CaSR agonist N-(3-[2-chlorophenyl]propyl)-(R)-alpha-methyl-3-methoxybenzylamine normalized Ca2+ propagation and E-cadherin organization after experimental wounding. These results suggest that age-related defects in CaSR expression dysregulate normal keratinocyte and epidermal Ca2+ signaling, leading to impaired E-cadherin expression, organization, and function. These findings show an innovative mechanism whereby Ca2+- and E-cadherin-dependent functions are impaired in aging epidermis and suggest a new therapeutic approach by restoring CaSR function.

Automated summary

Reduced expression of CaSR leads to impaired Ca2+ signal propagation in aged keratinocytes, with higher baseline cytosolic Ca2+ concentrations and lower capacitive Ca2+ entry in aged cells. Treatment with a CaSR agonist can normalize Ca2+ propagation and E-cadherin organization, suggesting a potential therapeutic approach by restoring CaSR function in aging skin cells.