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.
Cioffi
Donna L
DL
Department of Molecular and Cellular Pharmacology, Center for Lung Biology, University of South Alabama College of Medicine, Mobile, Alabama 36688, USA.
Stevens
Troy
T
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D050052:TRPC Cation Channels / Q000378:metabolism*
D050052:TRPC Cation Channels; D002118:Calcium