Calcium-Sensing Receptor Regulates Epidermal Intracellular Ca2+ Signaling and Re-Epithelialization after Wounding

Extracellular Ca2+ (Ca-o(2+)) is a crucial regulator of epidermal homeostasis and its receptor, the Ca2+ -sensing receptor (CaSR), conveys the Ca-o(2+) signals to promote keratinocyte adhesion, differentiation, and survival via activation of intracellular Ca2+ (Ca-i(2+)) and E-cadherinemediated signaling. Here, we took genetic loss-offunction approaches to delineate the functions of CaSR in wound re-epithelialization. Cutaneous injury triggered a robust CaSR expression and a surge of Ca-i(2+) in epidermis. CaSR and E-cadherin were co-expressed at the cellecell membrane between migratory keratinocytes in the nascent epithelial tongues. Blocking the expression of CaSR or E-cadherin in cultured keratinocytes markedly inhibited the wound-induced Ca-i(2) propagation and their ability to migrate collectively. Depleting CaSR also suppressed keratinocyte proliferation by downregulating the E-cadherin/epidermal growth factor receptor/mitogen-activated protein kinase signaling axis. Blunted epidermal Ca-i(2+) response to wounding and retarded wound healing were observed in the keratinocyte-specific CaSR knockout ((Epid)Casr(-/-)) mice, whose shortened neo-epithelia exhibited declined E-cadherin expression and diminished keratinocyte proliferation and differentiation. Conversely, stimulating endogenous CaSR with calcimimetic NPS-R568 accelerated wound re-epithelialization through enhancing the epidermal Ca-i(2+) signals and E-cadherin membrane expression. These findings demonstrated a critical role for the CaSR in epidermal regeneration and its therapeutic potential for improving skin wound repair.