Regulation of Endothelial Cell Barrier Function by Store‐Operated Calcium Entry

Transient receptor potential (TRP) channels fulfill important and diverse signaling functions, and are generally conserved among species. The canonical subfamily of TRP proteins, TRPC channels, possesses 7 isoforms that combine in various ways to form heteromultimers. In endothelium, TRPC1 and TRPC4 form subunits of a channel that selectively conducts calcium. This channel is activated by calcium depletion in the endoplasmic reticulum, and thus TRPC1/TRPC4 forms the molecular basis of a store operated calcium entry pathway. TRPC4 interacts with protein 4.1, which tethers the channel to the membrane skeleton and represents a gating mechanism required for calcium permeation. In response to inflammatory agonists such as thrombin and bradykinin, the generation of inositol 1,4,5-trisphosphate transiently depletes endoplasmic reticulum calcium and activates the TRPC1/TRPC4 channel. Calcium permeation through this channel triggers cytoskeletal reorganization that is necessary to disrupt the endothelial cell barrier and increase permeability. Thus, inhibition of the TRPC1/TRPC4 channel provides a putative anti-inflammatory strategy.