FIGURE 1.

STIM1 and Orai1 drive keratinocyte and melanocyte functions in the epidermis. Keratinocytes and melanocytes are critical protective cells in the epidermal layer (A). Keratinocytes proliferate in the basal layer and differentiate in response to elevated extracellular [Ca²⁺]. This is driven by the Ca²⁺-sensing receptor (CaSR) (B), which activates Gα_12/13 and Gα_q/11 proteins. ER Ca²⁺ mobilisation triggers SOCE, and the resultant cytosolic Ca²⁺ signals contribute to AP1 activation and differentiation (B). Large currents carried by TRPC channels accompany the Orai channel Ca²⁺ influx, although the mechanism of TRPC channel activation in keratinocytes is not understood. Melanocytes protect the body from ultraviolet radiation by secreting melanin granules into the surrounding tissue. This is controlled by two key pathways (C), each triggered by paracrine hormones secreted from the surrounding cells (C). α-Melanocyte stimulating hormone (αMSH) and endothelin-1 (ET-1) stimulate melanocyte-inducing transcription factor (MITF)-driven melanogenesis via Gα_s and Gα_q/11 pathways, respectively. Both pathways prompt IP₃-mediated ER Ca²⁺ store depletion and SOCE. Store depletion resulting from αMSH activity causes direct activation of adenylyl cyclase (AC6) by STIM1, producing a positive feedback loop where cyclic AMP production drives either protein kinase A (PKA) or EPAC activation to further activate phospholipase C (PLC), Ca²⁺ store depletion and SOCE.