Premium
The Isoc Channel is a Critical Determinant of Interendothelial Gap Formation
Author(s) -
Barry Christina Jean,
Cioffi Donna,
Stevens Troy
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.964.7
Subject(s) - thapsigargin , trpc , chemistry , microbiology and biotechnology , endoplasmic reticulum , biophysics , transient receptor potential channel , intracellular , gap junction , receptor , biology , biochemistry
Inflammatory agonists deplete Ca 2+ from the endoplasmic reticulum and activate Ca 2+ entry in a process referred to as store‐operated Ca 2+ entry (SOC). Activation of a Ca 2+ ‐selective SOC current, I soc, increases permeability and induces intercellular gap formation in pulmonary artery endothelial cells. However, the mechanism by which Ca 2+ entry through the I SOC leads to barrier disruption is unclear. Endothelial cells express the transient receptor potential canonical (TRPC) homologues 1 and 4 that contribute to the molecular basis of I SOC . TRPC4 specifically links the I soc channel to the membrane skeleton via interaction with protein 4.1. We therefore sought to determine whether inhibition of the TRPC4‐4.1 interaction is sufficient to prevent thapsigargin from inducing gaps. Thapsigargin activates SOC entry and induces a large rise in cytosolic Ca 2+ . Introduction of a competitive peptide that disrupts the TRPC4‐4.1 interaction reduces the global Ca 2+ response to thapsigargin and abolishes I soc. Moreover, peptide inhibition of the TRPC4‐4.1 interaction nearly abolished thapsigargin‐induced gap formation, and increased the rate of gap resealing. Thus, Ca 2+ entry through the I soc channel is critical to intercellular gap formation. Supported by HL60024.