Figure 4.

The molecular architecture of the I_CRAC-like channel in vascular endothelial cells. A series of studies carried out on rPAECs demonstrated that the ion channel signalplex mediating the endothelial I_CRAC−like currents is contributed to by one TRPC1 subunit and two TRPC4 subunits, as well as by Orai1, and is located within caveolae. TRPC4 is physically associated with both Orai1 and the actin-binding protein, protein 4.1. The latter, in turn, must be associated with the spectrin membrane skeleton (A). A reduction in [Ca²⁺]_ER (not shown) causes the STIM1-dependent activation of the ion channel signalplex on the PM (B). STIM1 is likely to physically interact with Orai1, TRPC1, and TRPC4, but this hypothesis remains to be experimentally probed. Orai1 incorporation into the STIM1/TRPC1/TRPC4 complex determines the Ca²⁺−selectivity of the store-operated current, which can therefore be defined as I_CRAC-like (C). For sake of clarity, the spectrin−F-actin network beneath the plasma membrane has not been shown in Panel B.