Channelpedia

PubMed 23045603


Referenced in Channelpedia wiki pages of: none

Automatically associated channels: TRP , TRPC , TRPC6



Title: TLR4 activation of TRPC6-dependent calcium signaling mediates endotoxin-induced lung vascular permeability and inflammation.

Authors: Mohammad Tauseef, Nebojsa Knezevic, Koteswara R Chava, Monica Smith, Sukriti Sukriti, Nicholas Gianaris, Alexander G Obukhov, Stephen M Vogel, Dean E Schraufnagel, Alexander Dietrich, Lutz Birnbaumer, Asrar B Malik, Dolly Mehta

Journal, date & volume: J. Exp. Med., 2012 Oct 22 , 209, 1953-68

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/23045603


Abstract
Lung vascular endothelial barrier disruption and the accompanying inflammation are primary pathogenic features of acute lung injury (ALI); however, the basis for the development of both remains unclear. Studies have shown that activation of transient receptor potential canonical (TRPC) channels induces Ca(2+) entry, which is essential for increased endothelial permeability. Here, we addressed the role of Toll-like receptor 4 (TLR4) intersection with TRPC6-dependent Ca(2+) signaling in endothelial cells (ECs) in mediating lung vascular leakage and inflammation. We find that the endotoxin (lipopolysaccharide; LPS) induces Ca(2+) entry in ECs in a TLR4-dependent manner. Moreover, deletion of TRPC6 renders mice resistant to endotoxin-induced barrier dysfunction and inflammation, and protects against sepsis-induced lethality. TRPC6 induces Ca(2+) entry in ECs, which is secondary to the generation of diacylglycerol (DAG) induced by LPS. Ca(2+) entry mediated by TRPC6, in turn, activates the nonmuscle myosin light chain kinase (MYLK), which not only increases lung vascular permeability but also serves as a scaffold to promote the interaction of myeloid differentiation factor 88 and IL-1R-associated kinase 4, which are required for NF-κB activation and lung inflammation. Our findings suggest that TRPC6-dependent Ca(2+) entry into ECs, secondary to TLR4-induced DAG generation, participates in mediating both lung vascular barrier disruption and inflammation induced by endotoxin.