In non-excitable cells the main mechanism of Ca²⁺ entry is "capacitative" or "store-operated" Ca²⁺ entry (SOCE). The fundamental idea of SOCE, which was first proposed in 1986, was that Ca²⁺ influx is regulated by the filling state of the intracellular Ca²⁺ stores. As the Ca²⁺ concentration falls, a signal, generated in the stores, opens store-operated Ca²⁺ channels (SOCs) in the plasma membrane. In the past few years there has been considerable interest in the possibility of transient receptor potential channels and Orai proteins functioning as SOCs and several models have been proposed to explain the communication between the Ca²⁺ stores and SOCs. One such model is conformational coupling that involves a direct protein-protein interaction between the inositol(1,4,5)trisphosphate receptors in the Ca²⁺ stores and SOCs in the plasma membrane. This interaction might be stable or occur de novo upon Ca²⁺ store depletion. Consistent with this, the Ca²⁺ sensor STIM1 located in the stores and plasma membrane could oligomerize bridging both structures. An alternative hypothesis assumes the generation of diffusible molecules that open SOCs. Diffusible messengers involved in SOC gating include cGMP, a product of cytochrome P450, such as 5,6-epoxyeicosatrienoic acid or a Ca²⁺

influx factor (CIF). A third model to explain the activation of SOCE is the translocation and insertion of preformed SOCs into the plasma membrane by vesicle fusion. In summary, multiple mechanisms might regulate SOCE in different, and even the same, cell types, the latter regulated by depletion of separate Ca²⁺ compartments. Supported by Junta Extremadura-Consejería Sanidad-Consumo (SCSS0619).