Figure 1.

[Ca²⁺]_o-stimulated signaling responses in keratinocytes. Membrane CaSR senses changes in [Ca²⁺]_o and activates two signaling pathways. One is mediated by the Ga_q-activated PLC, which generates IP₃ to trigger Ca²⁺ release from internal stores including ER and Golgi via IP₃R. Depletion of Ca²⁺ stores stimulates Ca²⁺ influx through SOCs by an IP₃R- and PLCγ1-mediated mechanism to further raise [Ca²⁺]_i. The second involves activation of Rho through interaction with Ga, e.g. Ga_q or Ga_12/13, filamin A, and RhoGEF to stimulate Fyn/Src kinases. Fyn/Src kinases phosphorylate catenins, promoting the formation of E-cadherin/catenin complex at the cell membrane and activation of PI3K. PI3K in turn activates PLCγ1 to further increase [Ca²⁺]_i. The activation of PI3K downstream effectors and rise in [Ca²⁺]_i stimulate the expression of genes essential for differentiation and cell survival. Finally, the intracellular CaSR forms complexes with IP₃R, PLCγ1, and SPCA1 in the Golgi and regulates Ca²⁺ uptake and release from intracellular Ca²⁺ stores, as well as Ca²⁺ entry via SOC.