title: Transient receptor potential channel 1 maintains adherens junction plasticity by suppressing sphingosine kinase 1 expression to induce endothelial hyperpermeability.
abstract: Stability of endothelial cell (EC) adherens junctions (AJs) is central for prevention of tissue edema, the hallmark of chronic inflammatory diseases including acute respiratory distress syndrome. Here, we demonstrate a previously unsuspected role of sphingosine kinase 1 (SPHK1) in the mechanism by which transient receptor potential channel 1 (Trpc1)-mediated Ca(2+) entry destabilizes AJs. Trpc1(-/-) monolayers showed a 2.2-fold increase in vascular endothelial (VE)-cadherin cell-surface expression above wild-type (WT) monolayers. Thrombin increased endothelial permeability (evident by a 5-fold increase in interendothelial gap area and 60% decrease in transendothelial electrical resistance) in WT but not Trpc1(-/-) ECs. Trpc1(-/-) mice resisted the hyperpermeability effects of the edemagenic agonists used and exhibited 60% less endotoxin-induced mortality. Because sphingosine-1-phosphate (S1P) strengthens AJs, we determined if TRPC1 functioned by inhibiting SPHK1 activity, which generates S1P. Intriguingly, Trpc1(-/-) ECs or ECs transducing a TRPC1-inactive mutant showed a 1.5-fold increase in basal SPHK1 expression compared with WT ECs, resulting in a 2-fold higher S1P level. SPHK1 inhibitor SK1-I decreased basal transendothelial electrical resistance more in WT ECs (48 and 72% reduction at 20 and 50 μM, respectively) than in Trpc1(-/-) ECs. However, SK1-I pretreatment rescued thrombin-induced EC permeability in Trpc1(-/-) ECs. Thus, TRPC1 suppression of basal SPHK1 activity enables EC-barrier destabilization by edemagenic agonists.
authors: Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois, USA.
authors: Mohammad
authors: M
authors: Tauseef
authors: Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois, USA.
authors: Mohammad
authors: M
authors: Farazuddin
authors: Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois, USA.
authors: Sukriti
authors: S
authors: Sukriti
authors: Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois, USA.
authors: Charu
authors: C
authors: Rajput
authors: Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois, USA.
authors: James Otto
authors: JO
authors: Meyer
authors: Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois, USA.
authors: Suresh Kumar
authors: SK
authors: Ramasamy
authors: Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois, USA dmehta@uic.edu.
authors: Dolly
authors: D
authors: Mehta
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism*; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002463:Cell Membrane Permeability; D042783:Endothelial Cells / Q000378:metabolism*; D004727:Endothelium / Q000378:metabolism*; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D000099157:Sphingosine Kinase
chemical_list: D015820:Cadherins; D002118:Calcium; D017853:Phosphotransferases (Alcohol Group Acceptor); D050052:TRPC Cation Channels; D000099157:Sphingosine Kinase; C096351:transient receptor potential cation channel, subfamily C, member 1
keywords: TRPC; VE-cadherin; acute lung injury; thrombin