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

Area of Science:

• Dermatology
• Cell Biology
• Molecular Biology

Background:

• Extracellular calcium (Ca²⁺_o) and its receptor, Ca²⁺-sensing receptor (CaSR), are key regulators of skin homeostasis.
• CaSR signaling influences keratinocyte adhesion, differentiation, and survival through intracellular calcium (Ca²⁺_i) and E-cadherin.

Purpose of the Study:

• To investigate the role of CaSR in wound re-epithelialization using genetic loss-of-function and gain-of-function approaches.
• To elucidate the molecular mechanisms by which CaSR influences keratinocyte behavior during skin repair.

Main Methods:

• Utilized genetic loss-of-function (keratinocyte-specific CaSR knockout mice) and pharmacological stimulation (NPS-R568).
• Assessed CaSR and E-cadherin expression, keratinocyte migration, proliferation, and differentiation in vitro and in vivo.
• Analyzed intracellular calcium (Ca²⁺_i) propagation and signaling pathways (EGFR/MAPK).

Main Results:

• Cutaneous injury induced CaSR expression and increased epidermal Ca²⁺_i.
• CaSR and E-cadherin co-localized at the membrane of migrating keratinocytes.
• Blocking CaSR or E-cadherin impaired keratinocyte migration and Ca²⁺_i propagation.
• CaSR depletion reduced keratinocyte proliferation via the E-cadherin/EGFR/MAPK axis.
• CaSR knockout mice showed delayed wound healing with reduced E-cadherin, proliferation, and differentiation.
• CaSR activation accelerated wound re-epithelialization by enhancing Ca²⁺_i signals and E-cadherin.

Conclusions:

• CaSR plays a critical role in epidermal regeneration and wound healing.
• CaSR signaling, coupled with E-cadherin, is essential for collective keratinocyte migration and proliferation.
• Targeting CaSR presents a potential therapeutic strategy for enhancing skin wound repair.