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Receptor Dimerization with EPCR Redirects PAR‐1 Signaling in Endothelial Cells
Author(s) -
McLaughlin Joseph N,
Malik Asrar B
Publication year - 2008
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.22.1_supplement.1178.2
Subject(s) - endothelial protein c receptor , protein c , thrombin , microbiology and biotechnology , receptor , transmembrane protein , chemistry , signal transduction , barrier function , endothelium , biology , biochemistry , immunology , endocrinology , platelet
Activated protein C (APC) is the only therapeutic shown to reduce mortality in patients with severe sepsis, however its mechanism of action remains unknown. An important possibility is that APC influences the activation of the G‐protein coupled thrombin receptor (PAR‐1) in the endothelium to promote barrier function. We propose that PAR‐1 signaling is regulated by direct interactions with the single transmembrane endothelial protein C receptor (EPCR), and that this co‐factor, not the proteolytic activity of thrombin or APC per se , determine whether PAR‐1 signaling is endothelial barrier‐disruptive or barrier‐protective. We postulate that the interaction of PAR‐1 with EPCR alters the G‐protein specificity of PAR‐1 by stabilizing a discrete active conformation. Toward this end we show here that PAR‐1 constitutively interacts with EPCR. However, the PAR‐1/EPCR complex is maintained only when PAR‐1 is activated by APC and not by thrombin. Hence EPCR may function as a critical molecular switch redirecting PAR‐1 signaling from endothelial barrier‐disruptive to barrier‐protective.