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A novel role of phosphatase and tensin homolog in regulating transient receptor potential channel 6‐mediated Ca2+‐entry and endothelial permeability
Author(s) -
Kini Vidisha,
Mehta Dolly
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.1178.4
Subject(s) - pten , tensin , phosphatase , microbiology and biotechnology , trpc6 , pdz domain , phosphatidylinositol , biology , chemistry , signal transduction , receptor , pi3k/akt/mtor pathway , transient receptor potential channel , phosphorylation , biochemistry
We recently showed that thrombin by binding to its receptor PAR‐1 activates transient receptor potential channel 6 (TRPC6), a receptor‐operated Ca 2+ channel (ROC), which in turn controls endothelial permeability. However, mechanisms regulating TRPC6 activity downstream of PAR‐1 remains unclear. Phosphatase and tensin homologue (PTEN) is a tumor suppressor, which dephosphorylates phosphatidylinositol 3,4,5‐triphosphate (PIP3) to maintain phosphatidylinositol 4,5‐biphosphate (PIP2) levels in the membrane. PTEN also contains a C‐terminal PDZ binding motif, known to be involved in mediating protein interaction. We addressed the hypothesis that PAR‐1 activates PTEN which in turn is required for TRPC6 activation and its anchoring to the plasma membrane and for signaling that results in the increased endothelial permeability. We show that PAR‐1 activation within seconds increased PTEN activity. Knock down of endogenous PTEN in endothelial cells markedly reduced Ca 2+ entry induced by thrombin as well as by DAG. However, knockdown of PTEN had no effect on thapsigargin induced Ca 2+ entry implicating that PTEN specifically regulates ROC activity. We observed that PTEN interacts with TRPC6 which increased after thrombin stimulation. The PTEN tail domain was required for mediating PTEN interaction with TRPC6. Transduction of a PTEN mutant lacking the tail domain and importantly the PDZ binding sequence abolished ROC activity. These findings identify a novel role of PTEN as a potential key regulatory switch responsible for G‐protein coupled receptor induced TRPC6 activation and its role in increased endothelial permeability.