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

Extracellular Ca²⁺ (Ca²⁺_o) is a crucial regulator of epidermal homeostasis and its receptor, the Ca²⁺-sensing receptor (CaSR), conveys the Ca²⁺_o signals to promote keratinocyte adhesion, differentiation, and survival via activation of intracellular Ca²⁺ (Ca²⁺_i) and E-cadherin-mediated signaling. Here, we took genetic loss-of-function approaches to delineate the functions of CaSR in wound re-epithelialization. Cutaneous injury triggered a robust CaSR expression and a surge of Ca²⁺_i in epidermis. CaSR and E-cadherin were co-expressed at the cell-cell 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 Ca²⁺_i 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 Ca²⁺_i response to wounding and retarded wound healing were observed in the keratinocyte-specific CaSR knockout (^EpidCasr^-/-) 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 Ca²⁺_i 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.