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


ABSTRACT: 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.

SUBMITTER: Tu CL 

PROVIDER: S-EPMC6431556 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Calcium-Sensing Receptor Regulates Epidermal Intracellular Ca<sup>2+</sup> Signaling and Re-Epithelialization after Wounding.

Tu Chia-Ling CL   Celli Anna A   Mauro Theodora T   Chang Wenhan W  

The Journal of investigative dermatology 20181104 4


Extracellular Ca<sup>2+</sup> (Ca<sup>2+</sup><sub>o</sub>) is a crucial regulator of epidermal homeostasis and its receptor, the Ca<sup>2+</sup>-sensing receptor (CaSR), conveys the Ca<sup>2+</sup><sub>o</sub> signals to promote keratinocyte adhesion, differentiation, and survival via activation of intracellular Ca<sup>2+</sup> (Ca<sup>2+</sup><sub>i</sub>) and E-cadherin-mediated signaling. Here, we took genetic loss-of-function approaches to delineate the functions of CaSR in wound re-epithel  ...[more]

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