DECREASED CALCIUM SENSING RECEPTOR EXPRESSION CONTROLS CALCIUM SIGNALING AND CELL-TO-CELL ADHESION DEFECTS IN AGED SKIN.

The Ca2+-sensing receptor (CaSR) drives essential Ca2+ and E-cadherin-mediated processes in the epidermis, including differentiation (Komuves et al., 2002), cell-to-cell adhesion (Tu et al., 2008) and epidermal barrier homeostasis in cells and young adult mice (Tunggal et al., 2005; Tu et al., 2012; Tu et al., 2019). We now report that decreased CaSR expression leads to impaired Ca2+ signal propagation in aged (>22 months) mouse epidermis and (>79 years donor age) human keratinocytes. Baseline cytosolic Ca2+ concentrations were higher, and capacitive Ca2+ entry was lower in aged vs. young keratinocytes, even though endoplasmic reticulum (ER) stores were largely intact. As in CaSR knockout mice (EpidCaSR-/-), decreased CaSR expression led to decreased E-cadherin, PLC γ expression and a compensatory upregulation of Stromal Interaction Molecule 1 (STIM1). Pretreatment with the CaSR agonist NPS-R568 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 illustrate a innovative mechanism whereby Ca2+ and E-cadherin-dependent functions are impaired in aging epidermis and suggest a new therapeutic approach by restoring CaSR function.