Figure 1.

Proposed models for I_CRAC, I_SOC, and I_CRAC−like currents. In the absence of extracellular stimulation, STIM1 is homogeneously distributed within ER cisternae, whereas Orai1, TRPC1, and TRPC4 are located on the PM. Upon depletion of the ER Ca²⁺ store, STIM1 aggregates and translocates in close apposition to the PM, thereby recruiting Orai1 hexamers into spatially confined puncta and activating the I_CRAC. Orai1−mediated extracellular Ca²⁺ entry can cause TRPC1 insertion into the plasma membrane (shown in Figure 2), thereby enabling TRPC1 activation by STIM1 and activating the I_SOC. Finally, STIM1 can determine the assembly of a complex ion channel signalplex consisting also of Orai1, TRPC1, and TRPC4 and responsible for the development of I_CRAC−like currents. As explained in Section 6.1, this supermolecular channel complex includes 1 TRPC1 subunit and 2 TRPC4 subunits. The lower current density of the I_CRAC as compared to the I_SOC and the I_CRAC-like current reflects the single-channel conductance of Orai1 channels, which is 1000-fold lower as compared to TRPC channels. The current density is defined by the ratio between the magnitude of an ion current, in pA, and the cell membrane capacitance, in pF.